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Mappings

MONDO

MONDO:0016030 Evans syndrome

MONDO:0016030 is the primary identifier for the syndrome. Note that its subclass tree is empty, so the primary/secondary and paediatric/adult distinctions this entry draws are clinical strata rather than ontology subtypes.

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Mechanistic Hypotheses

2

The CD4 to CD8 ratio as cause versus consequence

cd4-cd8-ratio-direction ALTERNATIVE

Evidence balance 1 support

A reduced CD4 to CD8 ratio is reported consistently in this syndrome, and the literature groups it with the molecular deficiencies as an explanation of pathophysiology. But an alternative reading is available and is not excluded by any cached source: chronic destruction of blood cells is itself a chronic antigenic stimulus, and an expanded cytotoxic compartment is what that would produce. The observation would look the same either way. This is recorded as ALTERNATIVE rather than folded into the main pathograph because the entry should not present a correlation as a direction.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Recent molecular theories explaining the physiopathology of ES include deficiencies of CTLA-4, LRBA, TPP2 and a decreased CD4/CD8 ratio."

The source calls these theories, and lists a cell-ratio observation alongside molecular deficiencies as though they were the same kind of claim. They are not, which is what this hypothesis records.

Evans syndrome as a presenting phenotype of an inborn error of immunity

es-as-iei-presentation EMERGING

Evidence balance 3 support

On this view Evans syndrome in a child is not a diagnosis but a presentation, and the real diagnosis is a named inborn error of immunity. It is EMERGING rather than CANONICAL because the yield is partial: in a prospective cohort referred specifically for this evaluation, the classic autoimmune lymphoproliferative syndrome was confirmed in 16 percent, leaving most patients without that label even after biomarker and genetic assessment.

Show evidence (3 references)

PMID:37735545 SUPPORT Human Clinical

"This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long-term immune suppression or splenectomy."

States the therapeutic consequence that makes the reclassification worth making.

PMID:38302222 SUPPORT Human Clinical

"After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients."

Supports the approach while bounding its yield at 16 percent, which is why the hypothesis is EMERGING rather than CANONICAL.

PMID:30349415 SUPPORT Human Clinical

"Interestingly, an association between ALPS and ES has been documented only in children."

Restricts the association to children, which is why this hypothesis is about paediatric-onset disease specifically.

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Pathophysiology

5

Loss of Lymphocyte Self-Tolerance

Mechanism confidence: Established

The unifying lesion, and the reason the syndrome is one disease rather than two coincident ones. Tolerance fails broadly enough that autoantibodies arise against more than one blood lineage. In children this failure increasingly has a named molecular cause in an inborn error of immunity; in adults it more often sits on lupus, a lymphoproliferative disorder or common variable immunodeficiency, and in half of cases no cause is found at all.

regulatory T cell CL:0000815 B cell CL:0000236

CTLA4 hgnc:2505 LRBA hgnc:1742 STAT3 hgnc:11364 KRAS hgnc:6407 FAS hgnc:11920

T cell homeostasis GO:0043029 ⚠ ABNORMAL

Downstream

Skewed T Cell Compartment The measurable cellular signature of the tolerance failure.

Systemic Lupus Erythematosus In children whose cytopenia is antinuclear antibody positive, the same tolerance failure declares itself later as systemic lupus. No cached source traces the steps between the cytopenia and the lupus, so the intermediates are left unstated; what the sources establish is the association and its restriction to the ANA-positive subgroup.

Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production Loss of regulatory constraint permits autoreactive B cells to mature and secrete antibody. The intermediate is the disturbed T cell compartment, which is curated separately.

Show evidence (3 references)

PMID:30349415 SUPPORT Human Clinical

"Several authors have proposed different disease pathways, summarized by the presence of immune dysregulation with antibodies against erythrocytes, platelets and/or granulocytes17 and decreased CD4:CD8 ratio."

States the two components of the unifying lesion together - multi-lineage autoantibodies and a disturbed T cell compartment.

PMID:30349415 SUPPORT Human Clinical

"CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary to a loss of T-cell homeostasis."

Names the molecular lesions found in paediatric cases and attributes them to loss of T cell homeostasis specifically, which is what this node represents.

PMID:30349415 SUPPORT Human Clinical

"autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a Fas gene mutation with an alteration in T-cell apoptoic pathways causing lymphoproliferation"

Sources the FAS route into this node - failure of the apoptotic pathway that deletes autoreactive lymphocytes is a loss of self-tolerance reached by a different lesion from the regulatory-brake genes. Quoted with the source's spelling of 'apoptoic'.

Skewed T Cell Compartment

Mechanism confidence: Provisional

A reduced CD4 to CD8 ratio, with fewer T helper and more cytotoxic T cells than in healthy controls. Recorded as PROVISIONAL because the observation is consistent across series but its causal position is not established: it may be the mechanism, a marker of it, or a consequence of chronic antigen exposure from ongoing cell destruction.

CD8-positive, alpha-beta T cell CL:0000625 regulatory T cell CL:0000815

T cell homeostasis GO:0043029 ⚠ ABNORMAL

Downstream

Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production The step from a disturbed T cell compartment to autoantibody-secreting B cells is not traced in any cached source, so the intermediates are left unstated rather than assumed from general immunology.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Abnormalities of immune regulation have been demonstrated in ES patients with a decreased level of T helper and increased T cytotoxic cells with a low CD4:CD8 ratio compared with healthy controls."

The primary observation, stated relative to a healthy control group.

Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production

Mechanism confidence: Established

Autoantibodies directed at erythrocytes, platelets and in some patients granulocytes. This is the node that makes Evans syndrome distinct from its components: the antibodies are lineage-specific and separate, so each cytopenia runs its own course, which is why one can remit while another relapses.

B cell CL:0000236 plasma cell CL:0000786

TPP2 hgnc:12016

B cell activation GO:0042113 ↑ INCREASED humoral immune response mediated by circulating immunoglobulin GO:0002455 ⚠ ABNORMAL

Downstream

Antibody-Mediated Erythrocyte Destruction Anti-erythrocyte antibody opsonises red cells for clearance.

Antibody-Mediated Platelet Destruction Anti-platelet antibody opsonises platelets for clearance.

Decreased Total Neutrophil Count Autoimmune neutropenia is the third and least common of the defining cytopenias. No cached source describes the clearance mechanism for granulocytes in this disease, so the intermediates are not asserted by analogy with the other two lineages.

Show evidence (2 references)

PMID:30349415 SUPPORT Human Clinical

"Several authors have proposed different disease pathways, summarized by the presence of immune dysregulation with antibodies against erythrocytes, platelets and/or granulocytes17 and decreased CD4:CD8 ratio."

Names all three antibody targets, which is what makes this a multi-lineage node rather than three separate diseases.

PMID:30349415 SUPPORT Human Clinical

"Serological analysis shows that the deficit of TPP2 is related to the presence of anti-nucleolar, anti-cytoplasmic, anti-nuclear antibodies and an increased level of age-associated B cells (ABCs)"

Places the TPP2 lesion at this node specifically - it is named for autoantibody excess and an expanded B cell subset rather than for loss of a regulatory brake.

Antibody-Mediated Erythrocyte Destruction

Mechanism confidence: Established

Opsonised erythrocytes are cleared by the reticuloendothelial system and by complement. The rate of destruction, not the antibody titre, is what produces the anaemia and the cardiovascular risk that dominates in older patients.

erythrocyte CL:0000232 macrophage CL:0000235

complement activation GO:0006956 ↑ INCREASED phagocytosis GO:0006909 ↑ INCREASED

Downstream

Coombs-Positive Hemolytic Anemia The clinical anaemia, with a positive direct antiglobulin test as its defining laboratory feature.

Jaundice Haemoglobin released by destroyed erythrocytes is catabolised to bilirubin. The intermediate is haemolysis itself, which this node represents.

Show evidence (1 reference)

PMID:40717001 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia."

Establishes autoimmune haemolytic anaemia as a defining component.

Antibody-Mediated Platelet Destruction

Mechanism confidence: Established

Opsonised platelets are cleared, chiefly in the spleen. That the spleen is the site of platelet clearance and less consistently the site of erythrocyte clearance is a testable prediction of this model, and the splenectomy data bear it out.

platelet CL:0000233 macrophage CL:0000235

phagocytosis GO:0006909 ↑ INCREASED

Downstream

Thrombocytopenia The clinical thrombocytopenia and its bleeding risk.

Mucocutaneous Bleeding The intermediate is the thrombocytopenia itself, curated separately as its own node. This is the platelet arm's clinical endpoint and the counterpart of the jaundice on the erythrocyte arm.

Show evidence (2 references)

PMID:40717001 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia."

Establishes immune thrombocytopenia as a defining component.

PMID:31594025 SUPPORT Human Clinical

"In particular, the rate of recurrent thrombocytopenia after splenectomy in patients with Evans syndrome was 42.8%, although interestingly there was no documented recurrence of autoimmune anemia in any of these patients."

The lineages diverge after splenectomy - thrombocytopenia recurs, anaemia does not. That dissociation is evidence that the two destruction pathways are separate rather than one process affecting two cell types.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Blood 5

Coombs-Positive Hemolytic Anemia VERY_FREQUENT HP:0004844

Show evidence (1 reference)

PMID:40717001 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia."

The "at least two of three" definition is what makes this near-universal but not obligate, and it is the basis for the band.

Thrombocytopenia VERY_FREQUENT HP:0001873

Show evidence (2 references)

PMID:40717001 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia."

Names immune thrombocytopenia among the three defining cytopenias.

PMID:37735545 SUPPORT Human Clinical

"Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia."

Gives the paediatric presentation sequence, in which thrombocytopenia usually comes first.

Decreased Total Neutrophil Count OCCASIONAL HP:0001875

Show evidence (1 reference)

PMID:19638626 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare disease characterized by the simultaneous or sequential development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or immune neutropenia."

The "and/or" construction places neutropenia as the optional third component, which is the basis for banding it one level lower. No cached source gives it a proportion.

Mucocutaneous Bleeding Abnormal bleeding HP:0001892

No frequency band, because the two cached sources make different claims. One lists the bleeding manifestations as part of the general clinical picture with no denominator; the other reports 12 of 42 children with a haemorrhagic complication, which is a severity claim rather than a prevalence one. Banding either as the frequency of bleeding would overstate what was measured. On the binding, `runoak -i ols:hp search "mucocutaneous bleeding"` and `search "mucosal hemorrhage"` both return nothing, and `search "bleeding"` returns HP:0011889 Bleeding with minor or no trauma as the nearest narrower candidate. That was rejected because neither source states the trauma context, so it would assert more than the quotes support. HP:0001892 covers the four named manifestations without adding a qualifier. The individual manifestations resolve (HP:0000967 Petechiae, HP:0031364 Ecchymosis, HP:0000225 Gingival bleeding, HP:0000421 Epistaxis) and could be split out if a source ever reports them with separate frequencies.

Show evidence (2 references)

PMID:30349415 SUPPORT Human Clinical

"Clinical features are associated with anemia and thrombocytopenia including pallor, weakness, fatigue, jaundice, petechiae, ecchymosis, gingivorrhagia and epistaxis."

Names the four bleeding manifestations and attributes them to the thrombocytopenia, which is what places this node on the platelet arm.

PMID:30349415 SUPPORT Human Clinical

"Twenty-four (58%) patients had complications – 12 hemorrhagic and 12 suffered severe infections, mainly sepsis, pneumonia, meningitis, abscess and osteomyelitis."

Gives a denominator for severe haemorrhagic complications in a paediatric series, which is a severity claim rather than the frequency of bleeding as such.

Increased Double-Negative T Cells Increased double-negative T cell number HP:0002851

Also unwired. The FAS lesion that produces this expansion is recorded on the root node, but no cached source states the step from that lesion to the expansion in a single sentence, so the edge is left out rather than inferred from general immunology.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"confirmed by the presence of elevated double-negative T-cells"

Ties the marker to the autoimmune lymphoproliferative syndrome overlap in a series where that overlap reached half of patients.

Digestive 1

Jaundice FREQUENT HP:0000952

Show evidence (1 reference)

PMID:40717001 SUPPORT Human Clinical

"Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia."

Establishes the haemolysis. The band is inferred from that rather than measured, which the description states rather than leaving implicit.

Immune 1

Severe and Recurrent Infections HP:0002719

Deliberately left causally unconnected. Both causes the sources give, chronic immunosuppressive therapy and the underlying immune deficit, sit outside this pathograph: the first is an effect of treatment rather than of the mechanism, and the second lies upstream of the tolerance failure the entry roots at. An edge from either destruction arm would assert a route no cached source describes, so the node is carried unwired rather than connected to keep a connectivity figure at 100 percent.

Show evidence (3 references)

PMID:30349415 SUPPORT Human Clinical

"Due to the prolonged immunosuppressive therapy and/or the associated underlying immune deficit, there is a risk of 66.6% of patients developing respiratory tract infections."

States both causes and gives a quantified respiratory infection risk, which is why this node is not wired to either destruction arm.

PMID:30349415 SUPPORT Human Clinical

"Twenty-four (58%) patients had complications – 12 hemorrhagic and 12 suffered severe infections, mainly sepsis, pneumonia, meningitis, abscess and osteomyelitis."

Names the infection types and gives their denominator in the same paediatric series.

PMID:33440924 SUPPORT Human Clinical

"Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most frequent cause was infection."

Makes infection the leading cause of death in the largest paediatric cohort, which is what raises this from a treatment side effect to a disease manifestation worth modelling.

Other 1

Systemic Lupus Erythematosus FREQUENT MONDO:0007915

Show evidence (2 references)

PMID:38227934 SUPPORT Human Clinical

"20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome."

Gives the progression rate for Evans syndrome against the two isolated cytopenias in one cohort, which is what makes the difference interpretable rather than a bare number.

PMID:38227934 SUPPORT Human Clinical

"None of the patients with ANA-negative test developed SLE."

Restricts the risk entirely to the ANA-positive subgroup, which is why the band is qualified in the description rather than applied to every patient.

🧬

Genetic Associations

6

CTLA4 (Haploinsufficiency with impaired regulatory T cell function)

Gene: CTLA4 hgnc:2505 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30349415 SUPPORT Human Clinical

"CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary to a loss of T-cell homeostasis."

Names CTLA-4 among the genes associated with the syndrome and attributes the mechanism to loss of T cell homeostasis.

PMID:30349415 SUPPORT Human Clinical

"CTLA-4 or CD152 is an inhibitory transmembrane receptor at the surface of regulatory T-cells that bind with a high affinity to CD80/CD86 molecules in antigen-presenting cells with subsequent endocytosis and downregulation contributing to immune homeostasis."

Gives the molecular function whose loss produces the phenotype.

LRBA (Deficiency causing secondary loss of CTLA-4 protein)

Gene: LRBA hgnc:1742 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30349415 SUPPORT Human Clinical

"LRBA is an intracellular protein that binds to CTLA-4 cytoplasmic fraction in regulatory T-cells following its endocytosis, avoiding its degradation."

States the mechanistic relationship between LRBA and CTLA-4 that makes the two deficiencies converge.

PMID:30349415 SUPPORT Human Clinical

"CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary to a loss of T-cell homeostasis."

Names LRBA among the associated genes in a paediatric cohort.

TPP2 (Deficiency with immunosenescence and autoantibody excess)

Gene: TPP2 hgnc:12016 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Recent molecular theories explaining the physiopathology of ES include deficiencies of CTLA-4, LRBA, TPP2 and a decreased CD4/CD8 ratio."

Names TPP2 among the molecular explanations advanced for the syndrome.

STAT3 (Gain-of-function variants with early-onset autoimmunity)

Gene: STAT3 hgnc:11364 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary to a loss of T-cell homeostasis."

Names STAT3 and specifies gain-of-function.

FAS (Defective lymphocyte apoptosis in autoimmune lymphoproliferative syndrome)

Gene: FAS hgnc:11920 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:41560547 SUPPORT Human Clinical

"Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS."

Names FAS among the commonest monogenic causes in a prospective autoimmune cytopenia cohort, alongside CTLA4 which is curated separately here.

KRAS (Activating variants in RAS-associated autoimmune leukoproliferative disease)

Gene: KRAS hgnc:6407 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary to a loss of T-cell homeostasis."

Names KRAS among the associated genes in the paediatric cohort.

💊

Medical Actions

8

Corticosteroid Therapy

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Platform: Small molecule

Prednisone is first-line for both cytopenias, with different durations and tapering schedules for the thrombocytopenia and the haemolytic anaemia. It works in about 80 percent of children initially, which is the problem: initial response is not the difficulty in this disease, durability is.

Mechanism Target:

INHIBITS Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production — Broad suppression of lymphocyte activation and antibody production rather than action on any lineage-specific step, which is why one agent covers both cytopenias.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"As in other autoimmune cytopenias, there is no established evidence-based treatment and steroids are the first-line therapy, with intravenous immunoglobulin administered as a life-saving resource in cases of severe immune thrombocytopenic purpura manifestations."

Places steroids as first-line for the syndrome as a whole rather than for one cytopenia.

Show evidence (2 references)

PMID:26625877 SUPPORT Human Clinical

"Steroids, the first-choice therapy, are successful in about 80% of cases."

Gives the initial response rate in children, which is the number that makes relapse rather than response the clinical problem.

PMID:19638626 SUPPORT Human Clinical

"All patients were given corticosteroids, but 50 of them (73%) required at least one "second-line" treatment, including splenectomy(n = 19) and rituximab (n = 11)."

Supports corticosteroids as universal first-line practice while recording that 73 percent still needed a second line, which is the limit on their durability.

Intravenous Immunoglobulin

Action: intravenous immunoglobulin therapy Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Other

Used alongside steroids as a rescue measure in severe thrombocytopenic bleeding rather than as maintenance. Modality is OTHER because pooled polyclonal immunoglobulin is neither a small molecule nor a monoclonal antibody nor replacement of a protein the patient cannot make.

Mechanism Target:

INHIBITS Antibody-Mediated Platelet Destruction — Acts on the clearance of opsonised platelets rather than on the autoantibody that opsonises them, which is why the effect is rapid and short-lived.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"As in other autoimmune cytopenias, there is no established evidence-based treatment and steroids are the first-line therapy, with intravenous immunoglobulin administered as a life-saving resource in cases of severe immune thrombocytopenic purpura manifestations."

Restricts the indication to severe thrombocytopenic manifestations, which is why this treatment targets the platelet arm and not the erythrocyte arm.

Show evidence (1 reference)

PMID:38968944 SUPPORT Human Clinical

"The panellists recommended extensive clinical and laboratory diagnostic tests, including bone marrow evaluation and CT scan, and an aggressive front-line therapy with prednisone (with or without intravenous immunoglobulins), with different treatment durations and tapering for immune..."

Places immunoglobulin as an optional addition to front-line prednisone in the adult consensus.

Rituximab

Action: biological therapy Ontology label: Biological Therapy NCIT:C15187

Agent: rituximab NCIT:C1702

Platform: Monoclonal antibody

An anti-CD20 antibody that depletes the B cells producing the autoantibodies, so it acts one node upstream of the steroids. It has largely displaced splenectomy as second-line therapy. The adult consensus discourages it in patients with immunodeficiency or severe infection, which matters here specifically because immunodeficiency is one of the commonest underlying disorders in this syndrome.

Mechanism Target:

INHIBITS Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production — Depletes CD20-positive B cells, removing the source of the autoantibodies against all affected lineages at once.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Rituximab is a chimeric anti-CD20 targeted drug that has been increasingly used as the second-line treatment in steroid-refractory or relapsing ES."

Names the target and the line of therapy.

Show evidence (3 references)

PMID:30349415 SUPPORT Human Clinical

"Recently, splenectomy has been replaced by rituximab due to the risks of the surgical procedure."

Records the displacement of splenectomy, which is the main change in second-line practice.

PMID:28444729 SUPPORT Human Clinical

"Forty-six patients responded (75%) and the 6-year relapse-free survival (RFS) was 48%."

The pattern this whole entry turns on, stated in one sentence. Three quarters respond and under half are still in remission at six years.

PMID:38968944 REFUTE Human Clinical

"However, rituximab was discouraged for patients with immunodeficiency or severe infections, with the same applying to splenectomy."

Carried as REFUTE because it is a recommendation against this treatment in a defined group, and that group - patients with immunodeficiency - overlaps heavily with the secondary Evans syndrome population.

Sirolimus

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

An mTOR inhibitor, singled out for children whose Evans syndrome sits on autoimmune lymphoproliferative syndrome. That is the clearest example in this entry of the genetic diagnosis changing the treatment rather than merely labelling it.

Mechanism Target:

MODULATES Skewed T Cell Compartment — Acts on the T cell compartment rather than on antibody production, which is why it is preferred where the underlying lesion is lymphoproliferative rather than humoral.

Show evidence (1 reference)

PMID:26625877 SUPPORT Human Clinical

"For children who are resistant, relapse or become steroid-dependent, rituximab is considered a valid second-line treatment, with the exception of those with an underlying diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such as mycophenolate mofetil and sirolimus."

Makes the choice between rituximab and sirolimus turn on the underlying diagnosis, which is what places sirolimus on the T cell node rather than the B cell node.

Show evidence (3 references)

PMID:26504182 SUPPORT Human Clinical

"We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS."

Prospective trial data in this syndrome specifically, with the important qualification that the response is slower than in the lymphoproliferative group where sirolimus works best.

PMID:26504182 SUPPORT Human Clinical

"All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus."

The contrast that justifies directing children with a lymphoproliferative diagnosis to this agent rather than to rituximab.

PMID:30349415 SUPPORT Human Clinical

"Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate, cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists."

Places sirolimus among the second-line options for refractory disease.

Mycophenolate Mofetil

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: mycophenolate mofetil CHEBI:8764

Platform: Small molecule

An antiproliferative immunosuppressant, named alongside sirolimus as the preferred option in children with underlying autoimmune lymphoproliferative syndrome. The adult consensus has moved the immunosuppressive agents as a class to third line or later.

Mechanism Target:

INHIBITS Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production — Blocks lymphocyte proliferation, reducing the expansion of the autoreactive clones rather than depleting those already present.

Show evidence (1 reference)

PMID:26625877 SUPPORT Human Clinical

"For children who are resistant, relapse or become steroid-dependent, rituximab is considered a valid second-line treatment, with the exception of those with an underlying diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such as mycophenolate mofetil and sirolimus."

Names mycophenolate mofetil as a preferred option in the lymphoproliferative subgroup.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate, cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists."

Lists mycophenolate mofetil among the second-line options.

Thrombopoietin Receptor Agonist Therapy

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: eltrombopag NCIT:C62501

Platform: Small molecule

Recommended for chronic thrombocytopenia and specifically where previous severe infection makes further immunosuppression unattractive. It is the one treatment here that does not suppress immunity at all: it raises platelet production instead of reducing platelet destruction, which is why it is the option when infection is the limiting problem.

Mechanism Target:

MODULATES Thrombocytopenia — Increases platelet production to outpace destruction. It does nothing to the autoantibody or to the clearance mechanism, so it treats the count rather than the disease.

Show evidence (1 reference)

PMID:38968944 SUPPORT Human Clinical

"Thrombopoietin receptor agonists were recommended for chronic immune thrombocytopenia and in the case of previous grade 4 infection."

Gives both indications, the second of which is what makes this the non-suppressive alternative.

Show evidence (1 reference)

PMID:30349415 SUPPORT Human Clinical

"Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate, cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists."

Lists the class among second-line options for refractory disease.

Fostamatinib

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: fostamatinib NCIT:C95222

Platform: Small molecule

A spleen tyrosine kinase inhibitor, placed third line or later by the adult consensus but suggested earlier in patients with previous thrombotic events. It acts on the phagocyte rather than on the lymphocyte, blocking the signalling that follows Fc receptor engagement of an opsonised cell.

Mechanism Target:

INHIBITS Antibody-Mediated Platelet Destruction — Blocks the intracellular signal that follows Fc receptor engagement on the phagocyte, so the opsonised platelet is not ingested. The antibody remains.

Show evidence (1 reference)

PMID:38968944 SUPPORT Human Clinical

"Fostamatinib was recommended as third-line or further-line treatment and suggested as second-line therapy for patients with previous thrombotic events."

Gives the line of therapy and the exception, which is the whole of what the cached sources say about this agent in this disease.

Show evidence (1 reference)

PMID:38968944 SUPPORT Human Clinical

"Evans syndrome is a rare disease marked by a severe clinical course, high relapse rate, infectious and thrombotic complications, and sometimes fatal outcome."

Establishes the thrombotic complications that define the subgroup in which this agent is moved earlier.

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Platform: Surgery

Removal of the principal site of clearance of opsonised cells. Historically second-line, now largely displaced by rituximab. The Evans-specific data are what make this interesting: the initial response matches that of isolated immune thrombocytopenia, but the durability does not, and the failure is lineage-specific.

Mechanism Target:

INHIBITS Antibody-Mediated Platelet Destruction — Removes the site where opsonised platelets are cleared. It does not touch the autoantibody, which is the likeliest reason the response is not durable.

Show evidence (1 reference)

PMID:31594025 SUPPORT Human Clinical

"In the Evans cohort, splenectomy led to an 85.7% initial response rate with a 42.8% rate of relapse within one year and a long-term (one-year) response rate of 42.8%."

Supports an effect on platelet clearance, and in the same numbers bounds it - 85.7 percent initially, 42.8 percent at one year.

Show evidence (2 references)

PMID:31594025 SUPPORT Human Clinical

"Our data suggest that long-term remission rates after splenectomy are lower in adults with Evans syndrome compared to those with ITP, although splenectomy may still be an acceptable treatment for certain patients with Evans syndrome."

The authors keep splenectomy as an acceptable option while stating that remission is less durable here than in isolated immune thrombocytopenia. The cohort was seven patients, so the estimate is imprecise.

PMID:30349415 SUPPORT Human Clinical

"Splenectomy was the only option in refractory relapsing patients before the introduction of rituximab, being classically considered as a second-line treatment in patients with autoimmune cytopenias, achieving a response of 60%–75% in AIHA and ITP,101 while in ES, the responses are documented to..."

An independent source giving a response range for this syndrome that starts at zero and tops out below the range reported for the isolated cytopenias.

🔬

Diagnosis

2

Extensive workup for an underlying disorder (PRESENT)

The adult consensus recommends bone marrow evaluation and CT imaging in every patient, not to confirm the cytopenias but to find the disorder underneath them. That is a direct consequence of the prognosis: secondary disease has a 5-year survival of 38 percent, so the search changes what happens next.

Show evidence (2 references)

PMID:38968944 SUPPORT Human Clinical

"The panellists recommended extensive clinical and laboratory diagnostic tests, including bone marrow evaluation and CT scan, and an aggressive front-line therapy with prednisone (with or without intravenous immunoglobulins), with different treatment durations and tapering for immune..."

States the recommended diagnostic scope and, in the same sentence, the front-line therapy that follows it.

PMID:31292991 SUPPORT Human Clinical

"Secondary Evans syndrome was associated with higher mortality rates than any of the other cohorts, with a 5-year survival of 38%."

Sources the survival figure quoted in this description, which is the reason the consensus asks for the underlying-disorder search rather than a confirmatory cytopenia workup.

Genetic evaluation in paediatric-onset disease (PRESENT)

In children the syndrome is increasingly treated as a presenting sign of an inborn error of immunity rather than a diagnosis in itself, and the point of finding the variant is that it changes the treatment from broad immune suppression to a targeted agent or transplant.

Show evidence (4 references)

PMID:37735545 SUPPORT Human Clinical

"This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders."

States the reclassification of paediatric cases by underlying molecular variant.

PMID:38302222 SUPPORT Human Clinical

"After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients."

Gives the yield for the classic diagnosis in a prospective cohort referred for exactly this evaluation, which bounds how often the search succeeds.

PMID:41560547 SUPPORT Human Clinical

"Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS."

A prospective cohort in which half of all autoimmune cytopenia patients showed evidence of an inborn error of immunity and a quarter had a monogenic cause, which is the strongest case for making this evaluation routine.

+ 1 more reference

📈

Progression

5

Established disease, adults

Median survival of 7.2 years in a nationwide adult cohort, and 1.7 years where the syndrome is secondary. This is the single most important number in the entry, because it is the one that separates Evans syndrome from the diseases it combines.

Show evidence (2 references)

PMID:31292991 SUPPORT Human Clinical

"The median survival with Evans syndrome was 7.2 years (primary Evans syndrome: 10.9 years; secondary Evans syndrome: 1.7 years)."

Gives overall and stratified median survival from a national registry.

PMID:31292991 SUPPORT Human Clinical

"Secondary Evans syndrome was associated with higher mortality rates than any of the other cohorts, with a 5-year survival of 38%."

The comparison groups are isolated immune thrombocytopenia, isolated haemolytic anaemia and the general population, which is what makes the figure interpretable.

After initial treatment response

Initial response rates match those of the isolated cytopenias. What differs is what happens afterwards, and that pattern holds across steroids, splenectomy and the syndrome as a whole.

Show evidence (2 references)

PMID:40717001 SUPPORT Human Clinical

"Observational studies suggest that although initial response rates to standard therapies are similar, long-term outcomes and mortality in ES are worse than in AIHA and ITP."

States the dissociation between initial response and long-term outcome directly.

PMID:19638626 SUPPORT Human Clinical

"At time of analysis, after a mean follow-up of 4.8 years, only 22 patients (32%) were in remission off treatment; 16 (24%) had died."

Quantifies both ends of the outcome distribution in the largest adult series.

Ten to twenty years after paediatric onset

The French national cohort followed paediatric-onset patients for a median of 11.3 years and separates two things that are usually conflated: the cytopenias largely remit, and the disease does not. Immunopathological manifestations accumulate with age on a rising curve, and survival at fifteen years is 84 percent.

Show evidence (4 references)

PMID:33440924 SUPPORT Human Clinical

"At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively."

The cytopenias themselves largely remit, and the haemolytic component remits more often than the thrombocytopenia. That asymmetry matches the lineage-specific splenectomy finding recorded elsewhere in this entry.

PMID:33440924 SUPPORT Human Clinical

"The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM)."

The immunopathology accumulates while the cytopenias are remitting, which is the basis for treating paediatric Evans syndrome as an ongoing immune disease rather than a resolved haematological one.

PMID:33440924 SUPPORT Human Clinical

"Survival at 15 years after diagnosis was 84%."

Gives paediatric survival directly, which is otherwise inferable only from hazard ratios.

+ 1 more reference

Adulthood after paediatric onset

Resolution of the blood counts does not mean resolution of the disease. Paediatric patients continue to declare immune manifestations into adulthood, which is the argument for transition programmes rather than discharge.

Show evidence (1 reference)

PMID:37735545 SUPPORT Human Clinical

"Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias."

Gives the proportion and makes explicit that it happens despite the cytopenias resolving.

Childhood

The Danish paediatric cohort finds reduced long-term survival and more splenectomy than in comparison groups, so the poor prognosis is not confined to older adults with secondary disease.

Show evidence (2 references)

PMID:32271826 SUPPORT Human Clinical

"We found that ES in children below 13 years of age is associated with reduced long term survival and increased rate of splenectomy."

States both findings for the paediatric population from a national registry.

PMID:32271826 SUPPORT Human Clinical

"Hazard ratio for death was 22 fold higher for children with ES compared to matched children from general population, and was also elevated compared to children with autoimmune haemolytic anaemia or immune thrombocytopenia."

Gives the magnitude relative to two reference groups. The comparison with the isolated cytopenias is what shows the excess is specific to the syndrome and not to autoimmune cytopenia generally.

📊

Prevalence

2

Denmark, adults

Point Prevalence 2.13 per 100,000 1–9 per 1,000,000

21.3 per million persons in 2016, from a nationwide registry cohort of patients aged 13 and over. Incidence in the same year was 1.8 per million person-years. Both rose significantly across the study period.

Show evidence (1 reference)

PMID:31292991 SUPPORT Human Clinical

"The annual Evans syndrome incidence and prevalence rose significantly during the study period, to 1.8 per million person-years and 21.3 per million persons, respectively, in 2016."

Gives both the incidence and the prevalence with the year, from a nationwide denominator rather than a case series.

Denmark, children under 13

Annual Incidence 0.12 per 100,000 1–9 per 1,000,000 per year

0.5 to 1.2 per 1,000,000 person-years across 1981 to 2015, rising over the period. The band is recorded on the incidence measure rather than as a prevalence.

Show evidence (1 reference)

PMID:32271826 SUPPORT Human Clinical

"The incidence of Evans syndrome ranged between 0.5 and 1.2/1,000,000 person-years."

Gives the childhood incidence range directly, from the same national registry system as the adult figures.

🌍

Epidemiology

4

Rarity relative to its component cytopenias

Evans syndrome is an order of magnitude rarer than either of the diseases it combines, which is why most of what is known comes from small retrospective series rather than trials.

Show evidence (1 reference)

PMID:40717001 SUPPORT Human Clinical

"At an incidence of approximately 10 to 30 times lower than AIHA and ITP, respectively, ES has been historically overlooked"

Quantifies the rarity relative to the two component diseases, which is the reason the evidence base is thin.

Simultaneous versus sequential onset

The two cytopenias appear together in about half of adult cases and sequentially in the rest, so a patient presenting with one cytopenia may declare the syndrome years later.

Show evidence (1 reference)

PMID:19638626 SUPPORT Human Clinical

"both cytopenias occurred simultaneously in 37 cases (54.5%)"

Gives the proportion presenting simultaneously in the largest adult series, which is what makes sequential presentation the other half rather than an exception.

Primary versus secondary

Half of adult cases sit on an identifiable underlying disorder. The distinction is prognostic rather than descriptive, since secondary disease carries markedly worse survival.

Show evidence (1 reference)

PMID:19638626 SUPPORT Human Clinical

"ES was considered as "primary" in 34 patients (50%) but was associated with an underlying disorder in half of the cases, including mainly systemic lupus, lymphoproliferative disorders, and common variable immunodeficiency."

Names the three commonest associated disorders and gives the primary-secondary split in the largest adult series.

Age and sex at diagnosis in a nationwide adult cohort

A Danish nationwide registry cohort gives the demographic profile without the referral bias that affects tertiary-centre series.

Show evidence (1 reference)

PMID:31292991 SUPPORT Human Clinical

"51.2% were women, and 27.3% were classified as secondary Evans syndrome."

Population-level sex distribution and secondary proportion. The secondary proportion is lower than in the referral series above, which is what a registry denominator would predict.

{ }

Source YAML

click to show

name: Evans Syndrome
creation_date: '2026-09-10T00:20:00Z'
description: >-
  An acquired autoimmune disease defined by at least two of the three autoimmune
  cytopenias - immune thrombocytopenia, autoimmune haemolytic anaemia and
  autoimmune neutropenia - occurring simultaneously or sequentially in the same
  patient. The definition is deliberately combinatorial rather than mechanistic,
  which is the central difficulty of the entry: what unites the cytopenias is not
  a shared autoantigen but a shared failure of lymphocyte self-tolerance, with
  each lineage destroyed by its own antibody. That framing is what explains the
  clinical observations that set Evans syndrome apart from its component
  diseases. Initial response rates to standard therapy match those of isolated
  immune thrombocytopenia and haemolytic anaemia, but relapse is more frequent,
  splenectomy is less durable, and survival is worse. In children the syndrome is
  increasingly a presenting sign of an inborn error of immunity rather than a
  diagnosis in itself.
categories:
- Autoimmune Disease
- Hematologic Disease
- Immune Dysregulation Syndrome
parents:
- autoimmune hematologic disease
synonyms:
- ES
- Evans' syndrome
- autoimmune hemolytic anemia and autoimmune thrombocytopenia
- immune pancytopenia
epidemiology:
- name: Rarity relative to its component cytopenias
  description: >-
    Evans syndrome is an order of magnitude rarer than either of the diseases it
    combines, which is why most of what is known comes from small retrospective
    series rather than trials.
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'At an incidence of approximately 10 to 30 times lower than AIHA and ITP, respectively,
      ES has been historically overlooked'
    explanation: Quantifies the rarity relative to the two component diseases, which is the reason
      the evidence base is thin.
- name: Simultaneous versus sequential onset
  description: >-
    The two cytopenias appear together in about half of adult cases and
    sequentially in the rest, so a patient presenting with one cytopenia may
    declare the syndrome years later.
  evidence:
  - reference: PMID:19638626
    reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis
      of 68 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'both cytopenias occurred simultaneously in 37 cases (54.5%)'
    explanation: Gives the proportion presenting simultaneously in the largest adult series, which
      is what makes sequential presentation the other half rather than an exception.
- name: Primary versus secondary
  description: >-
    Half of adult cases sit on an identifiable underlying disorder. The
    distinction is prognostic rather than descriptive, since secondary disease
    carries markedly worse survival.
  evidence:
  - reference: PMID:19638626
    reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis
      of 68 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'ES was considered as "primary" in 34 patients (50%) but was associated with an underlying
      disorder in half of the cases, including mainly systemic lupus, lymphoproliferative disorders,
      and common variable immunodeficiency.'
    explanation: Names the three commonest associated disorders and gives the primary-secondary
      split in the largest adult series.
- name: Age and sex at diagnosis in a nationwide adult cohort
  description: >-
    A Danish nationwide registry cohort gives the demographic profile without the
    referral bias that affects tertiary-centre series.
  evidence:
  - reference: PMID:31292991
    reference_title: Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '51.2% were women, and 27.3% were classified as secondary Evans syndrome.'
    explanation: Population-level sex distribution and secondary proportion. The secondary
      proportion is lower than in the referral series above, which is what a registry denominator
      would predict.
prevalence:
- population: Denmark, adults
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 2.13
  notes: 21.3 per million persons in 2016, from a nationwide registry cohort of patients aged 13
    and over. Incidence in the same year was 1.8 per million person-years. Both rose significantly
    across the study period.
  evidence:
  - reference: PMID:31292991
    reference_title: Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The annual Evans syndrome incidence and prevalence rose significantly during the study
      period, to 1.8 per million person-years and 21.3 per million persons, respectively, in 2016.'
    explanation: Gives both the incidence and the prevalence with the year, from a nationwide
      denominator rather than a case series.
- population: Denmark, children under 13
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.12
  notes: 0.5 to 1.2 per 1,000,000 person-years across 1981 to 2015, rising over the period. The
    band is recorded on the incidence measure rather than as a prevalence.
  evidence:
  - reference: PMID:32271826
    reference_title: Evans syndrome in children below 13 years of age - A nationwide population-based cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The incidence of Evans syndrome ranged between 0.5 and 1.2/1,000,000 person-years.'
    explanation: Gives the childhood incidence range directly, from the same national registry
      system as the adult figures.
pathophysiology:
- name: Loss of Lymphocyte Self-Tolerance
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The unifying lesion, and the reason the syndrome is one disease rather than
    two coincident ones. Tolerance fails broadly enough that autoantibodies arise
    against more than one blood lineage. In children this failure increasingly has
    a named molecular cause in an inborn error of immunity; in adults it more often
    sits on lupus, a lymphoproliferative disorder or common variable
    immunodeficiency, and in half of cases no cause is found at all.
  genes:
  - preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  - preferred_term: LRBA
    term:
      id: hgnc:1742
      label: LRBA
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  - preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: T cell homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0043029
      label: T cell homeostasis
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Several authors have proposed different disease pathways, summarized by the presence
      of immune dysregulation with antibodies against erythrocytes, platelets and/or granulocytes17
      and decreased CD4:CD8 ratio.'
    explanation: States the two components of the unifying lesion together - multi-lineage
      autoantibodies and a disturbed T cell compartment.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary
      to a loss of T-cell homeostasis.'
    explanation: Names the molecular lesions found in paediatric cases and attributes them to loss
      of T cell homeostasis specifically, which is what this node represents.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a Fas
      gene mutation with an alteration in T-cell apoptoic pathways causing lymphoproliferation
    explanation: Sources the FAS route into this node - failure of the apoptotic pathway that
      deletes autoreactive lymphocytes is a loss of self-tolerance reached by a different lesion
      from the regulatory-brake genes. Quoted with the source's spelling of 'apoptoic'.
  downstream:
  - target: Skewed T Cell Compartment
    causal_link_type: DIRECT
    description: The measurable cellular signature of the tolerance failure.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Abnormalities of immune regulation have been demonstrated in ES patients with a
        decreased level of T helper and increased T cytotoxic cells with a low CD4:CD8 ratio compared
        with healthy controls.'
      explanation: Gives the direction of the shift against healthy controls.
  - target: Systemic Lupus Erythematosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: In children whose cytopenia is antinuclear antibody positive, the same tolerance
      failure declares itself later as systemic lupus. No cached source traces the steps between
      the cytopenia and the lupus, so the intermediates are left unstated; what the sources
      establish is the association and its restriction to the ANA-positive subgroup.
    evidence:
    - reference: PMID:38227934
      reference_title: Antinuclear antibody-associated autoimmune cytopenia in childhood is a risk factor for systemic lupus erythematosus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'None of the patients with ANA-negative test developed SLE.'
      explanation: The absolute restriction to the ANA-positive subgroup is what makes this a
        stratified link rather than a general property of the syndrome.
  - target: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of regulatory constraint permits autoreactive B cells to mature and secrete
      antibody. The intermediate is the disturbed T cell compartment, which is curated separately.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'CTLA-4 or CD152 is an inhibitory transmembrane receptor at the surface of regulatory
        T-cells that bind with a high affinity to CD80/CD86 molecules in antigen-presenting cells with
        subsequent endocytosis and downregulation contributing to immune homeostasis.'
      explanation: Describes the regulatory brake whose loss is the named mechanism in the CTLA-4
        and LRBA forms, which is what makes the intermediate known rather than assumed.
- name: Skewed T Cell Compartment
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A reduced CD4 to CD8 ratio, with fewer T helper and more cytotoxic T cells
    than in healthy controls. Recorded as PROVISIONAL because the observation is
    consistent across series but its causal position is not established: it may
    be the mechanism, a marker of it, or a consequence of chronic antigen
    exposure from ongoing cell destruction.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: T cell homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0043029
      label: T cell homeostasis
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Abnormalities of immune regulation have been demonstrated in ES patients with a
      decreased level of T helper and increased T cytotoxic cells with a low CD4:CD8 ratio compared
      with healthy controls.'
    explanation: The primary observation, stated relative to a healthy control group.
  downstream:
  - target: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The step from a disturbed T cell compartment to autoantibody-secreting B cells is
      not traced in any cached source, so the intermediates are left unstated rather than assumed
      from general immunology.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Recent molecular theories explaining the physiopathology of ES include deficiencies
        of CTLA-4, LRBA, TPP2 and a decreased CD4/CD8 ratio.'
      explanation: Groups the ratio with the molecular deficiencies as theories rather than
        established mechanism, which is why this link is left indirect.
- name: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Autoantibodies directed at erythrocytes, platelets and in some patients
    granulocytes. This is the node that makes Evans syndrome distinct from its
    components: the antibodies are lineage-specific and separate, so each cytopenia
    runs its own course, which is why one can remit while another relapses.
  genes:
  - preferred_term: TPP2
    description: Deficiency is reported with autoantibody excess and expanded age-associated B
      cells, which places this lesion at the autoantibody node rather than at the tolerance root.
    term:
      id: hgnc:12016
      label: TPP2
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: B cell activation
    modifier: INCREASED
    term:
      id: GO:0042113
      label: B cell activation
  - preferred_term: humoral immune response mediated by circulating immunoglobulin
    modifier: ABNORMAL
    term:
      id: GO:0002455
      label: humoral immune response mediated by circulating immunoglobulin
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Several authors have proposed different disease pathways, summarized by the presence
      of immune dysregulation with antibodies against erythrocytes, platelets and/or granulocytes17
      and decreased CD4:CD8 ratio.'
    explanation: Names all three antibody targets, which is what makes this a multi-lineage node
      rather than three separate diseases.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serological analysis shows that the deficit of TPP2 is related to the presence of
      anti-nucleolar, anti-cytoplasmic, anti-nuclear antibodies and an increased level of
      age-associated B cells (ABCs)
    explanation: Places the TPP2 lesion at this node specifically - it is named for autoantibody
      excess and an expanded B cell subset rather than for loss of a regulatory brake.
  downstream:
  - target: Antibody-Mediated Erythrocyte Destruction
    causal_link_type: DIRECT
    description: Anti-erythrocyte antibody opsonises red cells for clearance.
    evidence:
    - reference: PMID:40717001
      reference_title: Evans syndrome revisited.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
        at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
        hemolytic anemia (AIHA), and autoimmune neutropenia.'
      explanation: Names autoimmune haemolytic anaemia as one of the three defining cytopenias.
  - target: Antibody-Mediated Platelet Destruction
    causal_link_type: DIRECT
    description: Anti-platelet antibody opsonises platelets for clearance.
    evidence:
    - reference: PMID:40717001
      reference_title: Evans syndrome revisited.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
        at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
        hemolytic anemia (AIHA), and autoimmune neutropenia.'
      explanation: Names immune thrombocytopenia as one of the three defining cytopenias.
  - target: Decreased Total Neutrophil Count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Autoimmune neutropenia is the third and least common of the defining cytopenias.
      No cached source describes the clearance mechanism for granulocytes in this disease, so the
      intermediates are not asserted by analogy with the other two lineages.
    evidence:
    - reference: PMID:19638626
      reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the
        analysis of 68 cases.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare disease characterized by the simultaneous or sequential
        development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or
        immune neutropenia.'
      explanation: Includes immune neutropenia in the definition while making it the optional third
        element, which is why it is banded and linked more cautiously than the other two.
- name: Antibody-Mediated Erythrocyte Destruction
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Opsonised erythrocytes are cleared by the reticuloendothelial system and by
    complement. The rate of destruction, not the antibody titre, is what produces
    the anaemia and the cardiovascular risk that dominates in older patients.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: complement activation
    modifier: INCREASED
    term:
      id: GO:0006956
      label: complement activation
  - preferred_term: phagocytosis
    modifier: INCREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
      at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
      hemolytic anemia (AIHA), and autoimmune neutropenia.'
    explanation: Establishes autoimmune haemolytic anaemia as a defining component.
  downstream:
  - target: Coombs-Positive Hemolytic Anemia
    causal_link_type: DIRECT
    description: The clinical anaemia, with a positive direct antiglobulin test as its defining
      laboratory feature.
    evidence:
    - reference: PMID:19638626
      reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the
        analysis of 68 cases.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare disease characterized by the simultaneous or sequential
        development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or
        immune neutropenia.'
      explanation: Names autoimmune haemolytic anaemia as one of the two required cytopenias.
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Haemoglobin released by destroyed erythrocytes is catabolised to bilirubin. The
      intermediate is haemolysis itself, which this node represents.
    evidence:
    - reference: PMID:40717001
      reference_title: Evans syndrome revisited.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
        at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
        hemolytic anemia (AIHA), and autoimmune neutropenia.'
      explanation: Establishes the haemolysis from which the jaundice follows.
- name: Antibody-Mediated Platelet Destruction
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Opsonised platelets are cleared, chiefly in the spleen. That the spleen is
    the site of platelet clearance and less consistently the site of erythrocyte
    clearance is a testable prediction of this model, and the splenectomy data
    bear it out.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: phagocytosis
    modifier: INCREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
      at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
      hemolytic anemia (AIHA), and autoimmune neutropenia.'
    explanation: Establishes immune thrombocytopenia as a defining component.
  - reference: PMID:31594025
    reference_title: 'Long-term remission rates after splenectomy in adults with Evans syndrome compared to
      immune thrombocytopenia: A single-center retrospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In particular, the rate of recurrent thrombocytopenia after splenectomy in patients
      with Evans syndrome was 42.8%, although interestingly there was no documented recurrence of
      autoimmune anemia in any of these patients.'
    explanation: The lineages diverge after splenectomy - thrombocytopenia recurs, anaemia does
      not. That dissociation is evidence that the two destruction pathways are separate rather
      than one process affecting two cell types.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: The clinical thrombocytopenia and its bleeding risk.
    evidence:
    - reference: PMID:19638626
      reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the
        analysis of 68 cases.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evans syndrome (ES) is a rare disease characterized by the simultaneous or sequential
        development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or
        immune neutropenia.'
      explanation: Names immune thrombocytopenia as one of the two required cytopenias.
  - target: Mucocutaneous Bleeding
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The intermediate is the thrombocytopenia itself, curated separately as its
      own node. This is the platelet arm's clinical endpoint and the counterpart
      of the jaundice on the erythrocyte arm.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Clinical features are associated with anemia and thrombocytopenia including pallor,
        weakness, fatigue, jaundice, petechiae, ecchymosis, gingivorrhagia and epistaxis.'
      explanation: Attributes the bleeding manifestations to the thrombocytopenia, which is what
        makes this an edge from the platelet arm rather than a free-standing phenotype.
phenotypes:
- category: Hematologic
  name: Coombs-Positive Hemolytic Anemia
  frequency: VERY_FREQUENT
  description: >-
    Autoimmune haemolytic anaemia with a positive direct antiglobulin test. One of
    the two cytopenias that define the syndrome, so it is present in nearly every
    patient by construction; the band is VERY_FREQUENT rather than OBLIGATE
    because the definition permits thrombocytopenia plus neutropenia without
    anaemia.
  phenotype_term:
    preferred_term: Coombs-positive hemolytic anemia
    term:
      id: HP:0004844
      label: Coombs-positive hemolytic anemia
  diagnostic: true
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
      at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
      hemolytic anemia (AIHA), and autoimmune neutropenia.'
    explanation: The "at least two of three" definition is what makes this near-universal but not
      obligate, and it is the basis for the band.
- category: Hematologic
  name: Thrombocytopenia
  frequency: VERY_FREQUENT
  description: >-
    Immune thrombocytopenia, the second defining cytopenia. In children the
    syndrome is often first labelled as chronic immune thrombocytopenia, with the
    haemolytic component declaring itself later.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  diagnostic: true
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
      at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
      hemolytic anemia (AIHA), and autoimmune neutropenia.'
    explanation: Names immune thrombocytopenia among the three defining cytopenias.
  - reference: PMID:37735545
    reference_title: 'Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Since its first description by Evans in 1951, this syndrome has been linked to chronic
      immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia
      or neutropenia.'
    explanation: Gives the paediatric presentation sequence, in which thrombocytopenia usually
      comes first.
- category: Hematologic
  name: Decreased Total Neutrophil Count
  frequency: OCCASIONAL
  description: >-
    Autoimmune neutropenia, the third and optional element of the definition. It
    is banded a level below the other two because the definition requires any two
    of three and the other pair is far more common, not because a cached source
    gives it a denominator.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:19638626
    reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis
      of 68 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare disease characterized by the simultaneous or sequential
      development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or
      immune neutropenia.'
    explanation: The "and/or" construction places neutropenia as the optional third component,
      which is the basis for banding it one level lower. No cached source gives it a proportion.
- category: Constitutional
  name: Jaundice
  frequency: FREQUENT
  description: >-
    Jaundice from bilirubin released by ongoing haemolysis. Banded from the
    near-universal presence of the haemolytic component rather than from a
    reported proportion, and this is stated because no cached source counts it.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome (ES) is a rare acquired autoimmune disease defined by the presence of
      at least two of the three autoimmune cytopenias: immune thrombocytopenia (ITP), autoimmune
      hemolytic anemia (AIHA), and autoimmune neutropenia.'
    explanation: Establishes the haemolysis. The band is inferred from that rather than measured,
      which the description states rather than leaving implicit.
- category: Immunologic
  name: Systemic Lupus Erythematosus
  frequency: FREQUENT
  description: >-
    Progression to systemic lupus erythematosus in children whose autoimmune
    cytopenia is antinuclear antibody positive. This is the strongest example of
    the syndrome behaving as a stage rather than a diagnosis: 45 percent of
    ANA-positive paediatric Evans syndrome progressed to lupus, against 20 percent
    for chronic immune thrombocytopenia and 19 percent for isolated haemolytic
    anaemia in the same cohort. The band applies to the ANA-positive subgroup, not
    to all patients, and the description says so rather than letting the number
    stand unqualified.
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: MONDO:0007915
      label: systemic lupus erythematosus
  evidence:
  - reference: PMID:38227934
    reference_title: Antinuclear antibody-associated autoimmune cytopenia in childhood is a risk factor for systemic lupus erythematosus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia,
      and 45% of Evans syndrome.'
    explanation: Gives the progression rate for Evans syndrome against the two isolated cytopenias
      in one cohort, which is what makes the difference interpretable rather than a bare number.
  - reference: PMID:38227934
    reference_title: Antinuclear antibody-associated autoimmune cytopenia in childhood is a risk factor for systemic lupus erythematosus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'None of the patients with ANA-negative test developed SLE.'
    explanation: Restricts the risk entirely to the ANA-positive subgroup, which is why the band is
      qualified in the description rather than applied to every patient.
- category: Hematologic
  name: Mucocutaneous Bleeding
  description: >-
    Spontaneous bleeding into skin and mucous membranes: petechiae, ecchymoses,
    gingival bleeding and epistaxis. This is the clinical manifestation the
    platelet arm produces, and it is the counterpart of the jaundice the
    erythrocyte arm produces. The entry previously asserted the outcome, naming
    bleeding among the leading causes of death in progression, without modelling
    the manifestation.
  phenotype_term:
    preferred_term: Mucocutaneous bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  notes: >-
    No frequency band, because the two cached sources make different claims. One
    lists the bleeding manifestations as part of the general clinical picture
    with no denominator; the other reports 12 of 42 children with a haemorrhagic
    complication, which is a severity claim rather than a prevalence one. Banding
    either as the frequency of bleeding would overstate what was measured. On the
    binding, `runoak -i ols:hp search "mucocutaneous bleeding"` and `search
    "mucosal hemorrhage"` both return nothing, and `search "bleeding"` returns
    HP:0011889 Bleeding with minor or no trauma as the nearest narrower
    candidate. That was rejected because neither source states the trauma
    context, so it would assert more than the quotes support. HP:0001892 covers
    the four named manifestations without adding a qualifier. The individual
    manifestations resolve (HP:0000967 Petechiae, HP:0031364 Ecchymosis,
    HP:0000225 Gingival bleeding, HP:0000421 Epistaxis) and could be split out if
    a source ever reports them with separate frequencies.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Clinical features are associated with anemia and thrombocytopenia including pallor,
      weakness, fatigue, jaundice, petechiae, ecchymosis, gingivorrhagia and epistaxis.'
    explanation: Names the four bleeding manifestations and attributes them to the thrombocytopenia,
      which is what places this node on the platelet arm.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Twenty-four (58%) patients had complications – 12 hemorrhagic and 12 suffered severe
      infections, mainly sepsis, pneumonia, meningitis, abscess and osteomyelitis.'
    explanation: Gives a denominator for severe haemorrhagic complications in a paediatric series,
      which is a severity claim rather than the frequency of bleeding as such.
- category: Immunologic
  name: Severe and Recurrent Infections
  description: >-
    Sepsis, pneumonia, meningitis, abscess and osteomyelitis, arising from the
    prolonged immunosuppression the syndrome requires and from the underlying
    immune deficit in the cases that sit on an inborn error of immunity.
    Infection is the commonest cause of death in the largest paediatric cohort,
    which is the other half of the outcome claim the entry already makes in
    progression.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  notes: >-
    Deliberately left causally unconnected. Both causes the sources give, chronic
    immunosuppressive therapy and the underlying immune deficit, sit outside this
    pathograph: the first is an effect of treatment rather than of the mechanism,
    and the second lies upstream of the tolerance failure the entry roots at. An
    edge from either destruction arm would assert a route no cached source
    describes, so the node is carried unwired rather than connected to keep a
    connectivity figure at 100 percent.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Due to the prolonged immunosuppressive therapy and/or the associated underlying immune
      deficit, there is a risk of 66.6% of patients developing respiratory tract infections.'
    explanation: States both causes and gives a quantified respiratory infection risk, which is why
      this node is not wired to either destruction arm.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Twenty-four (58%) patients had complications – 12 hemorrhagic and 12 suffered severe
      infections, mainly sepsis, pneumonia, meningitis, abscess and osteomyelitis.'
    explanation: Names the infection types and gives their denominator in the same paediatric series.
  - reference: PMID:33440924
    reference_title: 'Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most
      frequent cause was infection.'
    explanation: Makes infection the leading cause of death in the largest paediatric cohort, which
      is what raises this from a treatment side effect to a disease manifestation worth modelling.
- category: Immunologic
  name: Increased Double-Negative T Cells
  description: >-
    Expanded CD4 and CD8 double-negative T cells, the laboratory marker of the
    autoimmune lymphoproliferative syndrome overlap. Its interest here is
    diagnostic rather than mechanistic: it is what identifies the patients whose
    Evans syndrome is the presenting face of an inborn error of immunity, which
    is the claim the emerging hypothesis in this entry makes.
  phenotype_term:
    preferred_term: Increased double-negative T cell number
    term:
      id: HP:0002851
      label: Increased double-negative T cell number
  notes: >-
    Also unwired. The FAS lesion that produces this expansion is recorded on the
    root node, but no cached source states the step from that lesion to the
    expansion in a single sentence, so the edge is left out rather than inferred
    from general immunology.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: confirmed by the presence of elevated double-negative T-cells
    explanation: Ties the marker to the autoimmune lymphoproliferative syndrome overlap in a series
      where that overlap reached half of patients.
genetic:
- name: CTLA4
  gene_term:
    preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Haploinsufficiency with impaired regulatory T cell function
  notes: >-
    CTLA-4 is the inhibitory receptor on regulatory T cells that strips CD80 and
    CD86 from antigen-presenting cells. Loss of that brake is one of the named
    routes to the loss of T cell homeostasis this entry models as its root node.
    Found in paediatric rather than adult-onset disease.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary
      to a loss of T-cell homeostasis.'
    explanation: Names CTLA-4 among the genes associated with the syndrome and attributes the
      mechanism to loss of T cell homeostasis.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4 or CD152 is an inhibitory transmembrane receptor at the surface of regulatory
      T-cells that bind with a high affinity to CD80/CD86 molecules in antigen-presenting cells with
      subsequent endocytosis and downregulation contributing to immune homeostasis.'
    explanation: Gives the molecular function whose loss produces the phenotype.
- name: LRBA
  gene_term:
    preferred_term: LRBA
    term:
      id: hgnc:1742
      label: LRBA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Deficiency causing secondary loss of CTLA-4 protein
  notes: >-
    LRBA deficiency phenocopies CTLA-4 haploinsufficiency by a different route:
    LRBA rescues endocytosed CTLA-4 from degradation, so losing it depletes the
    same brake without touching the CTLA4 gene. The two therefore belong together
    in this entry rather than as independent findings.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'LRBA is an intracellular protein that binds to CTLA-4 cytoplasmic fraction in
      regulatory T-cells following its endocytosis, avoiding its degradation.'
    explanation: States the mechanistic relationship between LRBA and CTLA-4 that makes the two
      deficiencies converge.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary
      to a loss of T-cell homeostasis.'
    explanation: Names LRBA among the associated genes in a paediatric cohort.
- name: TPP2
  gene_term:
    preferred_term: TPP2
    term:
      id: hgnc:12016
      label: TPP2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Deficiency with immunosenescence and autoantibody excess
  notes: >-
    A distinct route to the same endpoint. Rather than removing a regulatory
    brake, TPP2 deficiency drives premature immunosenescence, with age-associated
    B cells and raised autoantibody levels.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recent molecular theories explaining the physiopathology of ES include deficiencies of
      CTLA-4, LRBA, TPP2 and a decreased CD4/CD8 ratio.'
    explanation: Names TPP2 among the molecular explanations advanced for the syndrome.
- name: STAT3
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Gain-of-function variants with early-onset autoimmunity
  notes: >-
    Gain-of-function rather than loss, which is the opposite direction from the
    CTLA-4 and LRBA lesions and a reminder that the syndrome is a convergent
    endpoint rather than a single pathway.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary
      to a loss of T-cell homeostasis.'
    explanation: Names STAT3 and specifies gain-of-function.
- name: FAS
  gene_term:
    preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Defective lymphocyte apoptosis in autoimmune lymphoproliferative syndrome
  notes: >-
    The classic route, and the one with a treatment attached to it. FAS variants
    cause autoimmune lymphoproliferative syndrome, in which failure of lymphocyte
    apoptosis permits autoreactive clones to persist. Children with that
    underlying diagnosis are directed to sirolimus rather than rituximab.
  evidence:
  - reference: PMID:41560547
    reference_title: Investigating Biomarkers for Inborn Errors of Immunity in a Prospective Study of Patients With Autoimmune Cytopenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with
      monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in
      NFKB1, CTLA4, and FAS.'
    explanation: Names FAS among the commonest monogenic causes in a prospective autoimmune
      cytopenia cohort, alongside CTLA4 which is curated separately here.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  association: Activating variants in RAS-associated autoimmune leukoproliferative disease
  notes: >-
    Grouped with the germline lesions in the source, but the KRAS variants in this
    setting are somatic. The distinction matters for testing, since a germline
    panel on blood may still detect a somatic clone but a negative result does not
    exclude one.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'CTLA-4, LRBA, KRAS, STAT3 gain-of-function mutations are associated with ES secondary
      to a loss of T-cell homeostasis.'
    explanation: Names KRAS among the associated genes in the paediatric cohort.
diagnosis:
- name: Extensive workup for an underlying disorder
  presence: PRESENT
  description: >-
    The adult consensus recommends bone marrow evaluation and CT imaging in every
    patient, not to confirm the cytopenias but to find the disorder underneath
    them. That is a direct consequence of the prognosis: secondary disease has a
    5-year survival of 38 percent, so the search changes what happens next.
  evidence:
  - reference: PMID:38968944
    reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The panellists recommended extensive clinical and laboratory diagnostic tests,
      including bone marrow evaluation and CT scan, and an aggressive front-line therapy with
      prednisone (with or without intravenous immunoglobulins), with different treatment durations
      and tapering for immune thrombocytopenia and autoimmune haemolytic anaemias (AIHAs).'
    explanation: States the recommended diagnostic scope and, in the same sentence, the front-line
      therapy that follows it.
  - reference: PMID:31292991
    reference_title: Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Secondary Evans syndrome was associated with higher mortality rates than any of the
      other cohorts, with a 5-year survival of 38%.'
    explanation: Sources the survival figure quoted in this description, which is the reason the
      consensus asks for the underlying-disorder search rather than a confirmatory cytopenia workup.
- name: Genetic evaluation in paediatric-onset disease
  presence: PRESENT
  description: >-
    In children the syndrome is increasingly treated as a presenting sign of an
    inborn error of immunity rather than a diagnosis in itself, and the point of
    finding the variant is that it changes the treatment from broad immune
    suppression to a targeted agent or transplant.
  evidence:
  - reference: PMID:37735545
    reference_title: 'Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This paper presents a new view of ES based on recent advances in genomics which begin
      to classify patients based on their underlying molecular variants in previously described
      primary immune disorders.'
    explanation: States the reclassification of paediatric cases by underlying molecular variant.
  - reference: PMID:38302222
    reference_title: 'Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies
      (ALPID): a prospective cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was
      diagnosed in 71 (16%) patients.'
    explanation: Gives the yield for the classic diagnosis in a prospective cohort referred for
      exactly this evaluation, which bounds how often the search succeeds.
  - reference: PMID:41560547
    reference_title: Investigating Biomarkers for Inborn Errors of Immunity in a Prospective Study of Patients With Autoimmune Cytopenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with
      monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in
      NFKB1, CTLA4, and FAS.'
    explanation: A prospective cohort in which half of all autoimmune cytopenia patients showed
      evidence of an inborn error of immunity and a quarter had a monogenic cause, which is the
      strongest case for making this evaluation routine.
  - reference: PMID:37792884
    reference_title: Evaluating the prevalence of inborn errors of immunity in adults with chronic immune thrombocytopenia or Evans syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'No cases of IEI were identified despite a high representation of subjects with a
      personal history of autoimmunity'
    explanation: Carried as REFUTE because it argues against extending this recommendation to
      adults. An adult cohort screened on a broad inborn-errors panel found no fully penetrant
      case, which is why the diagnosis entry is scoped to paediatric-onset disease.
treatments:
- name: Corticosteroid Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Prednisone is first-line for both cytopenias, with different durations and
    tapering schedules for the thrombocytopenia and the haemolytic anaemia. It
    works in about 80 percent of children initially, which is the problem: initial
    response is not the difficulty in this disease, durability is.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
    treatment_effect: INHIBITS
    description: Broad suppression of lymphocyte activation and antibody production rather than
      action on any lineage-specific step, which is why one agent covers both cytopenias.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'As in other autoimmune cytopenias, there is no established evidence-based treatment
        and steroids are the first-line therapy, with intravenous immunoglobulin administered as a
        life-saving resource in cases of severe immune thrombocytopenic purpura manifestations.'
      explanation: Places steroids as first-line for the syndrome as a whole rather than for one
        cytopenia.
  evidence:
  - reference: PMID:26625877
    reference_title: How I manage Evans Syndrome and AIHA cases in children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Steroids, the first-choice therapy, are successful in about 80% of cases.'
    explanation: Gives the initial response rate in children, which is the number that makes
      relapse rather than response the clinical problem.
  - reference: PMID:19638626
    reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis
      of 68 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'All patients were given corticosteroids, but 50 of them (73%) required at least one
      "second-line" treatment, including splenectomy(n = 19) and rituximab (n = 11).'
    explanation: Supports corticosteroids as universal first-line practice while recording that 73
      percent still needed a second line, which is the limit on their durability.
- name: Intravenous Immunoglobulin
  therapeutic_modality: OTHER
  description: >-
    Used alongside steroids as a rescue measure in severe thrombocytopenic
    bleeding rather than as maintenance. Modality is OTHER because pooled
    polyclonal immunoglobulin is neither a small molecule nor a monoclonal
    antibody nor replacement of a protein the patient cannot make.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_mechanisms:
  - target: Antibody-Mediated Platelet Destruction
    treatment_effect: INHIBITS
    description: Acts on the clearance of opsonised platelets rather than on the autoantibody that
      opsonises them, which is why the effect is rapid and short-lived.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'As in other autoimmune cytopenias, there is no established evidence-based treatment
        and steroids are the first-line therapy, with intravenous immunoglobulin administered as a
        life-saving resource in cases of severe immune thrombocytopenic purpura manifestations.'
      explanation: Restricts the indication to severe thrombocytopenic manifestations, which is why
        this treatment targets the platelet arm and not the erythrocyte arm.
  evidence:
  - reference: PMID:38968944
    reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The panellists recommended extensive clinical and laboratory diagnostic tests,
      including bone marrow evaluation and CT scan, and an aggressive front-line therapy with
      prednisone (with or without intravenous immunoglobulins), with different treatment durations
      and tapering for immune thrombocytopenia and autoimmune haemolytic anaemias (AIHAs).'
    explanation: Places immunoglobulin as an optional addition to front-line prednisone in the
      adult consensus.
- name: Rituximab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    An anti-CD20 antibody that depletes the B cells producing the autoantibodies,
    so it acts one node upstream of the steroids. It has largely displaced
    splenectomy as second-line therapy. The adult consensus discourages it in
    patients with immunodeficiency or severe infection, which matters here
    specifically because immunodeficiency is one of the commonest underlying
    disorders in this syndrome.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
    treatment_effect: INHIBITS
    description: Depletes CD20-positive B cells, removing the source of the autoantibodies against
      all affected lineages at once.
    evidence:
    - reference: PMID:30349415
      reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Rituximab is a chimeric anti-CD20 targeted drug that has been increasingly used as
        the second-line treatment in steroid-refractory or relapsing ES.'
      explanation: Names the target and the line of therapy.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recently, splenectomy has been replaced by rituximab due to the risks of the surgical
      procedure.'
    explanation: Records the displacement of splenectomy, which is the main change in second-line
      practice.
  - reference: PMID:28444729
    reference_title: 'Benefits of rituximab as a second-line treatment for autoimmune haemolytic anaemia in children: a prospective French cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Forty-six patients responded (75%) and the 6-year relapse-free survival (RFS) was
      48%.'
    explanation: The pattern this whole entry turns on, stated in one sentence. Three quarters
      respond and under half are still in remission at six years.
  - reference: PMID:38968944
    reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'However, rituximab was discouraged for patients with immunodeficiency or severe
      infections, with the same applying to splenectomy.'
    explanation: Carried as REFUTE because it is a recommendation against this treatment in a
      defined group, and that group - patients with immunodeficiency - overlaps heavily with the
      secondary Evans syndrome population.
- name: Sirolimus
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An mTOR inhibitor, singled out for children whose Evans syndrome sits on
    autoimmune lymphoproliferative syndrome. That is the clearest example in this
    entry of the genetic diagnosis changing the treatment rather than merely
    labelling it.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Skewed T Cell Compartment
    treatment_effect: MODULATES
    description: Acts on the T cell compartment rather than on antibody production, which is why
      it is preferred where the underlying lesion is lymphoproliferative rather than humoral.
    evidence:
    - reference: PMID:26625877
      reference_title: How I manage Evans Syndrome and AIHA cases in children.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'For children who are resistant, relapse or become steroid-dependent, rituximab is
        considered a valid second-line treatment, with the exception of those with an underlying
        diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such
        as mycophenolate mofetil and sirolimus.'
      explanation: Makes the choice between rituximab and sirolimus turn on the underlying
        diagnosis, which is what places sirolimus on the T cell node rather than the B cell node.
  evidence:
  - reference: PMID:26504182
    reference_title: 'Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We also treated 12 patients with multilineage cytopenias secondary to common variable
      immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most
      achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS.'
    explanation: Prospective trial data in this syndrome specifically, with the important
      qualification that the response is slower than in the lymphoproliferative group where
      sirolimus works best.
  - reference: PMID:26504182
    reference_title: 'Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a
      durable complete response (CR), including rapid improvement in autoimmune disease,
      lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus.'
    explanation: The contrast that justifies directing children with a lymphoproliferative
      diagnosis to this agent rather than to rituximab.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate,
      cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists.'
    explanation: Places sirolimus among the second-line options for refractory disease.
- name: Mycophenolate Mofetil
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An antiproliferative immunosuppressant, named alongside sirolimus as the
    preferred option in children with underlying autoimmune lymphoproliferative
    syndrome. The adult consensus has moved the immunosuppressive agents as a
    class to third line or later.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  target_mechanisms:
  - target: Autoreactive B Cell Activation and Multi-Lineage Autoantibody Production
    treatment_effect: INHIBITS
    description: Blocks lymphocyte proliferation, reducing the expansion of the autoreactive clones
      rather than depleting those already present.
    evidence:
    - reference: PMID:26625877
      reference_title: How I manage Evans Syndrome and AIHA cases in children.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'For children who are resistant, relapse or become steroid-dependent, rituximab is
        considered a valid second-line treatment, with the exception of those with an underlying
        diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such
        as mycophenolate mofetil and sirolimus.'
      explanation: Names mycophenolate mofetil as a preferred option in the lymphoproliferative
        subgroup.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate,
      cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists.'
    explanation: Lists mycophenolate mofetil among the second-line options.
- name: Thrombopoietin Receptor Agonist Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Recommended for chronic thrombocytopenia and specifically where previous
    severe infection makes further immunosuppression unattractive. It is the one
    treatment here that does not suppress immunity at all: it raises platelet
    production instead of reducing platelet destruction, which is why it is the
    option when infection is the limiting problem.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eltrombopag
      term:
        id: NCIT:C62501
        label: Eltrombopag Olamine
  target_mechanisms:
  - target: Thrombocytopenia
    treatment_effect: MODULATES
    description: Increases platelet production to outpace destruction. It does nothing to the
      autoantibody or to the clearance mechanism, so it treats the count rather than the disease.
    evidence:
    - reference: PMID:38968944
      reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Thrombopoietin receptor agonists were recommended for chronic immune thrombocytopenia
        and in the case of previous grade 4 infection.'
      explanation: Gives both indications, the second of which is what makes this the non-suppressive
        alternative.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate,
      cyclosporine, vincristine, azathioprine, sirolimus and thrombopoietin receptor agonists.'
    explanation: Lists the class among second-line options for refractory disease.
- name: Fostamatinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A spleen tyrosine kinase inhibitor, placed third line or later by the adult
    consensus but suggested earlier in patients with previous thrombotic events.
    It acts on the phagocyte rather than on the lymphocyte, blocking the signalling
    that follows Fc receptor engagement of an opsonised cell.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fostamatinib
      term:
        id: NCIT:C95222
        label: Fostamatinib
  target_mechanisms:
  - target: Antibody-Mediated Platelet Destruction
    treatment_effect: INHIBITS
    description: Blocks the intracellular signal that follows Fc receptor engagement on the
      phagocyte, so the opsonised platelet is not ingested. The antibody remains.
    evidence:
    - reference: PMID:38968944
      reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Fostamatinib was recommended as third-line or further-line treatment and suggested as
        second-line therapy for patients with previous thrombotic events.'
      explanation: Gives the line of therapy and the exception, which is the whole of what the
        cached sources say about this agent in this disease.
  evidence:
  - reference: PMID:38968944
    reference_title: 'Diagnosis and management of Evans syndrome in adults: first consensus recommendations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evans syndrome is a rare disease marked by a severe clinical course, high relapse rate,
      infectious and thrombotic complications, and sometimes fatal outcome.'
    explanation: Establishes the thrombotic complications that define the subgroup in which this
      agent is moved earlier.
- name: Splenectomy
  therapeutic_modality: SURGERY
  description: >-
    Removal of the principal site of clearance of opsonised cells. Historically
    second-line, now largely displaced by rituximab. The Evans-specific data are
    what make this interesting: the initial response matches that of isolated
    immune thrombocytopenia, but the durability does not, and the failure is
    lineage-specific.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Antibody-Mediated Platelet Destruction
    treatment_effect: INHIBITS
    description: Removes the site where opsonised platelets are cleared. It does not touch the
      autoantibody, which is the likeliest reason the response is not durable.
    evidence:
    - reference: PMID:31594025
      reference_title: 'Long-term remission rates after splenectomy in adults with Evans syndrome compared to
        immune thrombocytopenia: A single-center retrospective study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In the Evans cohort, splenectomy led to an 85.7% initial response rate with a 42.8%
        rate of relapse within one year and a long-term (one-year) response rate of 42.8%.'
      explanation: Supports an effect on platelet clearance, and in the same numbers bounds it - 85.7
        percent initially, 42.8 percent at one year.
  evidence:
  - reference: PMID:31594025
    reference_title: 'Long-term remission rates after splenectomy in adults with Evans syndrome compared to
      immune thrombocytopenia: A single-center retrospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our data suggest that long-term remission rates after splenectomy are lower in adults
      with Evans syndrome compared to those with ITP, although splenectomy may still be an acceptable
      treatment for certain patients with Evans syndrome.'
    explanation: The authors keep splenectomy as an acceptable option while stating that remission is
      less durable here than in isolated immune thrombocytopenia. The cohort was seven patients, so
      the estimate is imprecise.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Splenectomy was the only option in refractory relapsing patients before the introduction
      of rituximab, being classically considered as a second-line treatment in patients with autoimmune
      cytopenias, achieving a response of 60%–75% in AIHA and ITP,101 while in ES, the responses are
      documented to be considerably heterogeneous, between 0% and 66%.'
    explanation: An independent source giving a response range for this syndrome that starts at zero
      and tops out below the range reported for the isolated cytopenias.
progression:
- phase: Established disease, adults
  notes: >-
    Median survival of 7.2 years in a nationwide adult cohort, and 1.7 years where
    the syndrome is secondary. This is the single most important number in the
    entry, because it is the one that separates Evans syndrome from the diseases
    it combines.
  evidence:
  - reference: PMID:31292991
    reference_title: Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The median survival with Evans syndrome was 7.2 years (primary Evans syndrome: 10.9
      years; secondary Evans syndrome: 1.7 years).'
    explanation: Gives overall and stratified median survival from a national registry.
  - reference: PMID:31292991
    reference_title: Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Secondary Evans syndrome was associated with higher mortality rates than any of the
      other cohorts, with a 5-year survival of 38%.'
    explanation: The comparison groups are isolated immune thrombocytopenia, isolated haemolytic
      anaemia and the general population, which is what makes the figure interpretable.
- phase: After initial treatment response
  notes: >-
    Initial response rates match those of the isolated cytopenias. What differs is
    what happens afterwards, and that pattern holds across steroids, splenectomy
    and the syndrome as a whole.
  evidence:
  - reference: PMID:40717001
    reference_title: Evans syndrome revisited.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Observational studies suggest that although initial response rates to standard
      therapies are similar, long-term outcomes and mortality in ES are worse than in AIHA and ITP.'
    explanation: States the dissociation between initial response and long-term outcome directly.
  - reference: PMID:19638626
    reference_title: 'The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis
      of 68 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'At time of analysis, after a mean follow-up of 4.8 years, only 22 patients (32%) were
      in remission off treatment; 16 (24%) had died.'
    explanation: Quantifies both ends of the outcome distribution in the largest adult series.
- phase: Ten to twenty years after paediatric onset
  notes: >-
    The French national cohort followed paediatric-onset patients for a median of
    11.3 years and separates two things that are usually conflated: the cytopenias
    largely remit, and the disease does not. Immunopathological manifestations
    accumulate with age on a rising curve, and survival at fifteen years is 84
    percent.
  evidence:
  - reference: PMID:33440924
    reference_title: 'Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of
      patients, respectively.'
    explanation: The cytopenias themselves largely remit, and the haemolytic component remits more
      often than the thrombocytopenia. That asymmetry matches the lineage-specific splenectomy
      finding recorded elsewhere in this entry.
  - reference: PMID:33440924
    reference_title: 'Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The frequency and number of clinical and biological IM increased with age: at the
      age of 20 years, 74% had at least one clinical IM (cIM).'
    explanation: The immunopathology accumulates while the cytopenias are remitting, which is the
      basis for treating paediatric Evans syndrome as an ongoing immune disease rather than a
      resolved haematological one.
  - reference: PMID:33440924
    reference_title: 'Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Survival at 15 years after diagnosis was 84%.'
    explanation: Gives paediatric survival directly, which is otherwise inferable only from hazard
      ratios.
  - reference: PMID:26484337
    reference_title: 'Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Overall, 69% of children required one or more second-line immune treatments'
    explanation: Quantifies the treatment burden in children, matching the 73 percent figure
      recorded for adults and showing the pattern is not age-specific.
- phase: Adulthood after paediatric onset
  notes: >-
    Resolution of the blood counts does not mean resolution of the disease.
    Paediatric patients continue to declare immune manifestations into adulthood,
    which is the argument for transition programmes rather than discharge.
  evidence:
  - reference: PMID:37735545
    reference_title: 'Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Importantly, recent studies of the full lifespan of ES suggest that at least 80% of
      those paediatric patients will progress to various clinical or biological immunopathological
      manifestations with age despite the resolution of their cytopenias.'
    explanation: Gives the proportion and makes explicit that it happens despite the cytopenias
      resolving.
- phase: Childhood
  notes: >-
    The Danish paediatric cohort finds reduced long-term survival and more
    splenectomy than in comparison groups, so the poor prognosis is not confined
    to older adults with secondary disease.
  evidence:
  - reference: PMID:32271826
    reference_title: Evans syndrome in children below 13 years of age - A nationwide population-based cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We found that ES in children below 13 years of age is associated with reduced long term
      survival and increased rate of splenectomy.'
    explanation: States both findings for the paediatric population from a national registry.
  - reference: PMID:32271826
    reference_title: Evans syndrome in children below 13 years of age - A nationwide population-based cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Hazard ratio for death was 22 fold higher for children with ES compared to matched
      children from general population, and was also elevated compared to children with autoimmune
      haemolytic anaemia or immune thrombocytopenia.'
    explanation: Gives the magnitude relative to two reference groups. The comparison with the
      isolated cytopenias is what shows the excess is specific to the syndrome and not to autoimmune
      cytopenia generally.
mechanistic_hypotheses:
- hypothesis_group_id: cd4-cd8-ratio-direction
  hypothesis_label: The CD4 to CD8 ratio as cause versus consequence
  status: ALTERNATIVE
  description: >-
    A reduced CD4 to CD8 ratio is reported consistently in this syndrome, and the
    literature groups it with the molecular deficiencies as an explanation of
    pathophysiology. But an alternative reading is available and is not excluded by
    any cached source: chronic destruction of blood cells is itself a chronic
    antigenic stimulus, and an expanded cytotoxic compartment is what that would
    produce. The observation would look the same either way. This is recorded as
    ALTERNATIVE rather than folded into the main pathograph because the entry should
    not present a correlation as a direction.
  evidence:
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recent molecular theories explaining the physiopathology of ES include deficiencies of
      CTLA-4, LRBA, TPP2 and a decreased CD4/CD8 ratio.'
    explanation: The source calls these theories, and lists a cell-ratio observation alongside
      molecular deficiencies as though they were the same kind of claim. They are not, which is what
      this hypothesis records.
- hypothesis_group_id: es-as-iei-presentation
  hypothesis_label: Evans syndrome as a presenting phenotype of an inborn error of immunity
  status: EMERGING
  description: >-
    On this view Evans syndrome in a child is not a diagnosis but a presentation,
    and the real diagnosis is a named inborn error of immunity. It is EMERGING
    rather than CANONICAL because the yield is partial: in a prospective cohort
    referred specifically for this evaluation, the classic autoimmune
    lymphoproliferative syndrome was confirmed in 16 percent, leaving most patients
    without that label even after biomarker and genetic assessment.
  evidence:
  - reference: PMID:37735545
    reference_title: 'Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This has opened up new avenues of targeted therapy or bone marrow transplant at rather
      than broad long-term immune suppression or splenectomy.'
    explanation: States the therapeutic consequence that makes the reclassification worth making.
  - reference: PMID:38302222
    reference_title: 'Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies
      (ALPID): a prospective cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was
      diagnosed in 71 (16%) patients.'
    explanation: Supports the approach while bounding its yield at 16 percent, which is why the
      hypothesis is EMERGING rather than CANONICAL.
  - reference: PMID:30349415
    reference_title: 'Evans syndrome: clinical perspectives, biological insights and treatment modalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Interestingly, an association between ALPS and ES has been documented only in children.'
    explanation: Restricts the association to children, which is why this hypothesis is about
      paediatric-onset disease specifically.
references:
- reference: PMID:19638626
  title: "The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases."
- reference: PMID:26484337
  title: "Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort."
- reference: PMID:26504182
  title: "Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial."
- reference: PMID:26625877
  title: "How I manage Evans Syndrome and AIHA cases in children."
- reference: PMID:28444729
  title: "Benefits of rituximab as a second-line treatment for autoimmune haemolytic anaemia in children: a prospective French cohort study."
- reference: PMID:30349415
  title: "Evans syndrome: clinical perspectives, biological insights and treatment modalities."
- reference: PMID:31292991
  title: "Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort."
- reference: PMID:31594025
  title: "Long-term remission rates after splenectomy in adults with Evans syndrome compared to immune thrombocytopenia: A single-center retrospective study."
- reference: PMID:32271826
  title: "Evans syndrome in children below 13 years of age - A nationwide population-based cohort study."
- reference: PMID:33440924
  title: "Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden."
- reference: PMID:37735545
  title: "Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia."
- reference: PMID:37792884
  title: "Evaluating the prevalence of inborn errors of immunity in adults with chronic immune thrombocytopenia or Evans syndrome."
- reference: PMID:38227934
  title: "Antinuclear antibody-associated autoimmune cytopenia in childhood is a risk factor for systemic lupus erythematosus."
- reference: PMID:38302222
  title: "Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study."
- reference: PMID:38968944
  title: "Diagnosis and management of Evans syndrome in adults: first consensus recommendations."
- reference: PMID:40717001
  title: "Evans syndrome revisited."
- reference: PMID:41560547
  title: "Investigating Biomarkers for Inborn Errors of Immunity in a Prospective Study of Patients With Autoimmune Cytopenia."
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016030
      label: Evans syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0016030 is the primary identifier for the syndrome. Note that its subclass tree is
      empty, so the primary/secondary and paediatric/adult distinctions this entry draws are
      clinical strata rather than ontology subtypes.
disease_term:
  preferred_term: Evans syndrome
  term:
    id: MONDO:0016030
    label: Evans syndrome
notes: >-
  The definitional problem, and why it shapes the whole entry. Evans syndrome is
  defined by a combination of findings rather than by a mechanism: any two of
  immune thrombocytopenia, autoimmune haemolytic anaemia and autoimmune
  neutropenia. That is a diagnosis of co-occurrence, and it raises the question of
  whether the syndrome is one disease or two that happen to share a patient. The
  pathograph here takes a position on that. It puts a single root - loss of
  lymphocyte self-tolerance - above two separate destruction pathways, one per
  lineage, each with its own antibody. The claim is that the tolerance failure is
  shared and the effector mechanisms are not.

  That structure makes a prediction, and the splenectomy data test it. After
  splenectomy in a small Evans cohort, thrombocytopenia recurred in 42.8 percent
  while autoimmune anaemia recurred in none. If one process were destroying both
  lineages, removing the clearance organ should affect both the same way. It did
  not. The cohort is seven patients and the observation should not be
  over-read, but it is the only lineage-resolved evidence in the cached sources
  and it is recorded on the platelet destruction node for that reason.

  What actually distinguishes this syndrome from its components is not the
  response to treatment but what follows it. Steroids work initially in about 80
  percent of children. Splenectomy produces an 85.7 percent initial response,
  statistically indistinguishable from the 90.9 percent in isolated immune
  thrombocytopenia in the same series. Then the curves separate: median survival
  of 7.2 years overall, 1.7 years where the disease is secondary, a 5-year
  survival of 38 percent in that group, and 24 percent dead at a mean follow-up of
  4.8 years in the largest adult series. Initial response is not the problem.

  A caution about the CD4 to CD8 ratio, recorded as an ALTERNATIVE hypothesis
  rather than buried. The literature lists a decreased ratio alongside CTLA-4,
  LRBA and TPP2 deficiency as "molecular theories explaining the physiopathology".
  Those are not the same kind of claim. A germline deficiency in a regulatory
  protein is a candidate cause; a shifted cell ratio in patients with ongoing
  cell destruction is an observation that chronic antigenic stimulation would also
  produce. The node for the skewed T cell compartment is marked PROVISIONAL for
  the same reason.

  The genetic section groups five genes that reach the same endpoint by different
  routes, and the differences are worth keeping visible. CTLA-4 haploinsufficiency
  removes a regulatory brake directly; LRBA deficiency removes the same brake
  indirectly, by failing to rescue endocytosed CTLA-4 from degradation, so the
  two converge without sharing a gene. STAT3 acts by gain of function, the
  opposite direction. TPP2 deficiency works through immunosenescence rather than
  through regulatory failure at all. KRAS is grouped with the germline lesions in
  the source but its variants in this setting are somatic, which changes what a
  negative germline panel means. The syndrome is a convergent endpoint, not a
  pathway.

  Why the entry has no subtypes. MONDO:0016030 has an empty subclass tree, and the
  distinctions that matter clinically - primary versus secondary, paediatric
  versus adult onset - are strata rather than ontology subtypes. They are carried
  in epidemiology, progression and the hypotheses instead of being invented as
  has_subtypes entries.

  Two treatments are recorded with recommendations against them as well as for
  them. Rituximab and splenectomy are both discouraged by the adult consensus in
  patients with immunodeficiency or severe infection. That caveat matters more here
  than it would in isolated immune thrombocytopenia, because common variable
  immunodeficiency is one of the three commonest disorders underlying secondary
  Evans syndrome. The REFUTE item on rituximab records that directly rather than
  leaving it in prose.

  What the deep-research job contributed, and what it did not. The job returned
  nine findings across seventeen citations, and seven of its PMIDs were not in the
  draft. Each was verified against PubMed and then fetched before use; two of its
  quoted sentences did not match the cached text and were replaced with the real
  wording rather than trusted. Its most useful contribution was the progression to
  systemic lupus, which no source in the original draft mentioned: in the French
  national cohort, 45 percent of antinuclear-antibody-positive paediatric Evans
  syndrome went on to lupus, against 20 percent for chronic immune
  thrombocytopenia and 19 percent for isolated haemolytic anaemia, and no
  ANA-negative patient did. That is a stratified risk, so it is banded for the
  ANA-positive subgroup and the description says so.

  The job also supplied the long-term paediatric outcome data, which separate two
  things usually run together: the cytopenias remit while the disease does not. At
  ten years, sustained complete remission was 54.5 percent for the
  thrombocytopenia and 78.4 percent for the haemolytic anaemia; by age twenty, 74
  percent had at least one clinical immunopathological manifestation. Survival at
  fifteen years was 84 percent.

  A note on the asymmetry, because it appears three times independently. The
  haemolytic component remits more often than the thrombocytopenia at ten years;
  thrombocytopenia recurs after splenectomy while the anaemia does not; and
  rituximab relapse-free survival is higher in isolated haemolytic anaemia than in
  Evans syndrome. None of these is decisive alone. Together they are the reason
  this entry models two separate destruction pathways under a shared root rather
  than one process acting on two cell types.

  On the yield of genetic evaluation, which the entry deliberately scopes by age.
  A prospective paediatric cohort found evidence of an inborn error of immunity in
  half of all autoimmune cytopenia patients and a monogenic cause in a quarter. An
  adult cohort screened on a broad inborn-errors panel found no fully penetrant
  case. That negative is carried as REFUTE evidence on the diagnosis entry rather
  than omitted, because it is what keeps the recommendation from being extended to
  adults on the strength of the paediatric data.

  Known extension points: thrombotic complications, which the adult consensus
  names but which no cached source quantifies in this syndrome; haematopoietic
  stem cell transplantation, which the cached review reports has been successful
  in cases unresponsive to immunosuppressive agents but without a cohort, a
  denominator or a response rate, so it is not curated as a treatment beside the
  eight that each carry one; the specific antibody targets on
  each lineage; abatacept for the CTLA-4 and LRBA forms, which the research report
  raises as genotype-directed therapy but which no cached source documents in this
  syndrome; the natural canine disease and the Fas-lpr mouse, both of which the
  report surfaced without a fetchable primary source in these caches; and partial
  DiGeorge syndrome and NFKB1, named in the same cohort sentence as CTLA4 and FAS
  but without enough detail here to curate as their own genetic entries.

  Provenance. Curated from PubMed with a five-iteration OpenScientist
  deep-research job as a cross-check, which ran for 908 seconds and returned 17
  citations. Content_type was checked on every cache before writing. Seven of the
  seventeen references are full text, and for those the Results sections were read
  rather than the abstracts alone.

📚

References & Deep Research

References

17

PMID:19638626

The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases.

No top-level findings curated for this source.

PMID:26484337

Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.

No top-level findings curated for this source.

PMID:26504182

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.

No top-level findings curated for this source.

PMID:26625877

How I manage Evans Syndrome and AIHA cases in children.

No top-level findings curated for this source.

PMID:28444729

Benefits of rituximab as a second-line treatment for autoimmune haemolytic anaemia in children: a prospective French cohort study.

No top-level findings curated for this source.

PMID:30349415

Evans syndrome: clinical perspectives, biological insights and treatment modalities.

No top-level findings curated for this source.

PMID:31292991

Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.

No top-level findings curated for this source.

PMID:31594025

Long-term remission rates after splenectomy in adults with Evans syndrome compared to immune thrombocytopenia: A single-center retrospective study.

No top-level findings curated for this source.

PMID:32271826

Evans syndrome in children below 13 years of age - A nationwide population-based cohort study.

No top-level findings curated for this source.

PMID:33440924

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

No top-level findings curated for this source.

PMID:37735545

Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.

No top-level findings curated for this source.

PMID:37792884

Evaluating the prevalence of inborn errors of immunity in adults with chronic immune thrombocytopenia or Evans syndrome.

No top-level findings curated for this source.

PMID:38227934

Antinuclear antibody-associated autoimmune cytopenia in childhood is a risk factor for systemic lupus erythematosus.

No top-level findings curated for this source.

PMID:38302222

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

No top-level findings curated for this source.

PMID:38968944

Diagnosis and management of Evans syndrome in adults: first consensus recommendations.

No top-level findings curated for this source.

PMID:40717001

Evans syndrome revisited.

No top-level findings curated for this source.

PMID:41560547

Investigating Biomarkers for Inborn Errors of Immunity in a Prospective Study of Patients With Autoimmune Cytopenia.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

The definitional problem, and why it shapes the whole entry. Evans syndrome is defined by a combination of findings rather than by a mechanism: any two of immune thrombocytopenia, autoimmune haemolytic anaemia and autoimmune neutropenia. That is a diagnosis of co-occurrence, and it raises the question of whether the syndrome is one disease or two that happen to share a patient. The pathograph here takes a position on that. It puts a single root - loss of lymphocyte self-tolerance - above two separate destruction pathways, one per lineage, each with its own antibody. The claim is that the tolerance failure is shared and the effector mechanisms are not. That structure makes a prediction, and the splenectomy data test it. After splenectomy in a small Evans cohort, thrombocytopenia recurred in 42.8 percent while autoimmune anaemia recurred in none. If one process were destroying both lineages, removing the clearance organ should affect both the same way. It did not. The cohort is seven patients and the observation should not be over-read, but it is the only lineage-resolved evidence in the cached sources and it is recorded on the platelet destruction node for that reason. What actually distinguishes this syndrome from its components is not the response to treatment but what follows it. Steroids work initially in about 80 percent of children. Splenectomy produces an 85.7 percent initial response, statistically indistinguishable from the 90.9 percent in isolated immune thrombocytopenia in the same series. Then the curves separate: median survival of 7.2 years overall, 1.7 years where the disease is secondary, a 5-year survival of 38 percent in that group, and 24 percent dead at a mean follow-up of 4.8 years in the largest adult series. Initial response is not the problem. A caution about the CD4 to CD8 ratio, recorded as an ALTERNATIVE hypothesis rather than buried. The literature lists a decreased ratio alongside CTLA-4, LRBA and TPP2 deficiency as "molecular theories explaining the physiopathology". Those are not the same kind of claim. A germline deficiency in a regulatory protein is a candidate cause; a shifted cell ratio in patients with ongoing cell destruction is an observation that chronic antigenic stimulation would also produce. The node for the skewed T cell compartment is marked PROVISIONAL for the same reason. The genetic section groups five genes that reach the same endpoint by different routes, and the differences are worth keeping visible. CTLA-4 haploinsufficiency removes a regulatory brake directly; LRBA deficiency removes the same brake indirectly, by failing to rescue endocytosed CTLA-4 from degradation, so the two converge without sharing a gene. STAT3 acts by gain of function, the opposite direction. TPP2 deficiency works through immunosenescence rather than through regulatory failure at all. KRAS is grouped with the germline lesions in the source but its variants in this setting are somatic, which changes what a negative germline panel means. The syndrome is a convergent endpoint, not a pathway. Why the entry has no subtypes. MONDO:0016030 has an empty subclass tree, and the distinctions that matter clinically - primary versus secondary, paediatric versus adult onset - are strata rather than ontology subtypes. They are carried in epidemiology, progression and the hypotheses instead of being invented as has_subtypes entries. Two treatments are recorded with recommendations against them as well as for them. Rituximab and splenectomy are both discouraged by the adult consensus in patients with immunodeficiency or severe infection. That caveat matters more here than it would in isolated immune thrombocytopenia, because common variable immunodeficiency is one of the three commonest disorders underlying secondary Evans syndrome. The REFUTE item on rituximab records that directly rather than leaving it in prose. What the deep-research job contributed, and what it did not. The job returned nine findings across seventeen citations, and seven of its PMIDs were not in the draft. Each was verified against PubMed and then fetched before use; two of its quoted sentences did not match the cached text and were replaced with the real wording rather than trusted. Its most useful contribution was the progression to systemic lupus, which no source in the original draft mentioned: in the French national cohort, 45 percent of antinuclear-antibody-positive paediatric Evans syndrome went on to lupus, against 20 percent for chronic immune thrombocytopenia and 19 percent for isolated haemolytic anaemia, and no ANA-negative patient did. That is a stratified risk, so it is banded for the ANA-positive subgroup and the description says so. The job also supplied the long-term paediatric outcome data, which separate two things usually run together: the cytopenias remit while the disease does not. At ten years, sustained complete remission was 54.5 percent for the thrombocytopenia and 78.4 percent for the haemolytic anaemia; by age twenty, 74 percent had at least one clinical immunopathological manifestation. Survival at fifteen years was 84 percent. A note on the asymmetry, because it appears three times independently. The haemolytic component remits more often than the thrombocytopenia at ten years; thrombocytopenia recurs after splenectomy while the anaemia does not; and rituximab relapse-free survival is higher in isolated haemolytic anaemia than in Evans syndrome. None of these is decisive alone. Together they are the reason this entry models two separate destruction pathways under a shared root rather than one process acting on two cell types. On the yield of genetic evaluation, which the entry deliberately scopes by age. A prospective paediatric cohort found evidence of an inborn error of immunity in half of all autoimmune cytopenia patients and a monogenic cause in a quarter. An adult cohort screened on a broad inborn-errors panel found no fully penetrant case. That negative is carried as REFUTE evidence on the diagnosis entry rather than omitted, because it is what keeps the recommendation from being extended to adults on the strength of the paediatric data. Known extension points: thrombotic complications, which the adult consensus names but which no cached source quantifies in this syndrome; haematopoietic stem cell transplantation, which the cached review reports has been successful in cases unresponsive to immunosuppressive agents but without a cohort, a denominator or a response rate, so it is not curated as a treatment beside the eight that each carry one; the specific antibody targets on each lineage; abatacept for the CTLA-4 and LRBA forms, which the research report raises as genotype-directed therapy but which no cached source documents in this syndrome; the natural canine disease and the Fas-lpr mouse, both of which the report surfaced without a fetchable primary source in these caches; and partial DiGeorge syndrome and NFKB1, named in the same cohort sentence as CTLA4 and FAS but without enough detail here to curate as their own genetic entries. Provenance. Curated from PubMed with a five-iteration OpenScientist deep-research job as a cross-check, which ran for 908 seconds and returned 17 citations. Content_type was checked on every cache before writing. Seven of the seventeen references are full text, and for those the Results sections were read rather than the abstracts alone.

Create: Evans Syndrome MONDO:0016030 · 2026-09-10T13:53:54Z · View source

Created from PubMed literature with a five-iteration OpenScientist deep-research job as a cross-check. The job ran 908 seconds and returned nine findings across seventeen citations. Finding the gap took three attempts, which is worth recording because naive name matching keeps failing on this repository. Castleman disease looked like a gap on a label match and is in fact covered by three entries plus an open issue. The reliable method is subclass-closure of curated MONDO identifiers plus a filename check plus an open-issue scan, and Evans syndrome passes all three: MONDO:0016030 has an empty subclass tree, no curated entry references it, and no filename collides. The central curation decision is what to do with a disease defined by co-occurrence rather than by mechanism. Evans syndrome is any two of immune thrombocytopenia, autoimmune haemolytic anaemia and autoimmune neutropenia, which raises the question of whether it is one disease or two sharing a patient. The pathograph takes a position: a single root, loss of lymphocyte self-tolerance, above two separate destruction pathways, one per lineage, each with its own antibody. The tolerance failure is shared; the effector mechanisms are not. That structure makes a prediction, and three independent observations bear it out. After splenectomy, thrombocytopenia recurred in 42.8 percent while autoimmune anaemia recurred in none of the same seven patients. At ten years in the French paediatric cohort, sustained complete remission was 54.5 percent for the thrombocytopenia and 78.4 percent for the haemolytic anaemia. And rituximab relapse-free survival is higher in isolated haemolytic anaemia than in Evans syndrome. None is decisive alone; together they are the reason the entry does not model one process acting on two cell types. What distinguishes this syndrome from its components is not response but what follows it. Steroids work initially in about 80 percent of children; splenectomy gives an 85.7 percent initial response against 90.9 percent for isolated immune thrombocytopenia in the same series; rituximab gives 75 percent. Then the curves separate: median survival 7.2 years, 1.7 years where secondary, a 22-fold hazard ratio for death in children against matched controls, and 24 percent dead at a mean 4.8 years in the largest adult series. The entry says this in the description, in progression and in notes, because a reader who takes the response rates at face value will draw the wrong conclusion. The reduced CD4 to CD8 ratio is deliberately not treated as mechanism. The literature lists it alongside CTLA-4, LRBA and TPP2 deficiency as a molecular theory, but those are different kinds of claim: a germline deficiency in a regulatory protein is a candidate cause, while a shifted cell ratio in patients undergoing chronic cell destruction is something chronic antigenic stimulation would also produce. The node is PROVISIONAL and the alternative reading is recorded as an ALTERNATIVE mechanistic hypothesis rather than buried. Six genes are curated and the differences between them are kept visible, because the syndrome is a convergent endpoint rather than a pathway. CTLA-4 haploinsufficiency removes a regulatory brake directly; LRBA deficiency removes the same brake indirectly by failing to rescue endocytosed CTLA-4 from degradation, so the two converge without sharing a gene. STAT3 acts by gain of function, the opposite direction. TPP2 works through immunosenescence rather than regulatory failure. FAS causes failure of lymphocyte apoptosis and is the one lesion with a treatment attached, since children with that diagnosis are directed to sirolimus rather than rituximab. KRAS is grouped with the germline lesions in the source but its variants here are somatic, which changes what a negative germline panel means. The deep-research job earned its place. Seven of its PMIDs were not in the draft, and each was verified against PubMed and fetched before use. Two of its quoted sentences did not match the cached text and were replaced with the real wording rather than trusted; that is the second time in this series that verification has caught a report quote that did not survive contact with the source. Its most valuable contribution was progression to systemic lupus, which no source in the original draft mentioned: 45 percent of antinuclear-antibody-positive paediatric Evans syndrome progressed to lupus, against 20 and 19 percent for the isolated cytopenias, and no ANA-negative patient did. The band is scoped to the ANA-positive subgroup and the description says so rather than letting the number stand unqualified. The genetic evaluation recommendation is scoped by age on the evidence rather than by assumption. A prospective paediatric cohort found evidence of an inborn error of immunity in half of autoimmune cytopenia patients and a monogenic cause in a quarter; an adult cohort screened on a broad panel found no fully penetrant case. That negative is carried as REFUTE evidence on the diagnosis entry, because it is what stops the paediatric recommendation being extended to adults. No subtypes are declared. MONDO:0016030 has an empty subclass tree, and the distinctions that matter clinically - primary versus secondary, paediatric versus adult onset - are strata rather than ontology subtypes, so they are carried in epidemiology, progression and the hypotheses instead of being invented as has_subtypes entries. Validation: 80/80 snippets verified, term validation passes, all repository content gates pass, no mid-word truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets, weighted compliance 100.0 percent. Seventeen references, seven of them full text, content_type checked on every cache before writing.

OpenScientist ▸

Evans Syndrome: A Comprehensive Disease Characteristics Report

openscientist-autonomous 17 citations 2026-09-10T09:42:57.945125

Evans Syndrome: A Comprehensive Disease Characteristics Report

Disease: Evans syndrome MONDO ID: MONDO:0016030 · Orphanet: ORPHA:1959 · Category: Autoimmune cytopenia / immune dysregulation Report type: Literature-based disease knowledge-base entry (no primary datasets provided; all content derived from aggregated disease-level literature and cohort studies).

Summary

Evans syndrome (ES) is a rare autoimmune disorder defined by the concurrent or sequential occurrence of autoimmune hemolytic anemia (AIHA) — proven by a positive direct antiglobulin (Coombs) test with hemolysis — and immune thrombocytopenia (ITP), sometimes accompanied by autoimmune neutropenia. It is a diagnosis of exclusion, established with a complete blood count, blood smear, and Coombs test after secondary causes have been ruled out. The final common effector mechanism is production of warm IgG autoantibodies against erythrocyte antigens and anti-platelet glycoprotein antibodies, leading to Fc-receptor– and complement-mediated destruction of red cells and platelets, predominantly in the spleen.

The central insight consolidated across this investigation is that Evans syndrome is best understood not as an isolated blood disorder but as a phenotype of systemic immune dysregulation. In children especially, ES is frequently the presenting manifestation of an underlying inborn error of immunity (IEI) — with monogenic or immune-dysregulation causes identified in roughly 50–60% of pediatric autoimmune-cytopenia cohorts (ALPS/FAS pathway, CTLA4, LRBA, PIK3CD/APDS, NFKB1, SASH3, partial DiGeorge syndrome). It may also be secondary to systemic lupus erythematosus (SLE), lymphoproliferative disease, or common variable immunodeficiency. ANA positivity in childhood ES is a strong predictor of progression to SLE.

The clinical course is chronic and relapsing with substantial morbidity and mortality. Nationwide registry data give an adult incidence approaching ~1.8 per million person-years and a median survival of ~7 years overall (dramatically worse — ~1.7 years — for secondary ES). Pediatric-onset disease carries ~16% mortality at 15 years, most often from infection or bleeding, with a very high treatment burden. Management escalates from corticosteroids/IVIG (first-line) to rituximab and sirolimus (steroid-sparing second-line), with genotype-directed targeted immunotherapy (abatacept, leniolisib, JAK inhibitors) increasingly important. This report details all 15 disease-characteristic domains, flagging where evidence is robust versus where it is sparse or not applicable.

Key Findings

F001 — Definition: coexistence of AIHA and ITP

Evans syndrome is consistently defined across cohorts as the simultaneous or sequential association of AIHA (positive direct antiglobulin/Coombs test with hemolysis) and ITP. The two events may occur at the same time or one may follow the other. Diagnosis relies on a full blood count/film and a Coombs test, and is a diagnosis of exclusion after secondary causes are ruled out. In the French OBS'CEREVANCE pediatric AIHA cohort (n=265), Evans syndrome was present in 37% of childhood AIHA cases.

"There is a coexistence of Immune thrombocytopenia (ITP) with Autoimmune haemolytic anaemia (AIHA) and both of these events may occur simultaneously or one follows the other." — PMID: 31983745 "Evans' syndrome was diagnosed in 37% of cases." — PMID: 21228033

F002 — Frequently the presenting sign of an inborn error of immunity (IEI)

In a Tampa Bay prospective autoimmune cytopenia (AIC) cohort (n=104), 51% showed evidence of IEI and 26% had monogenic disorders; IEI prevalence was highest in Evans syndrome (61.5%) and AIHA (62.5%). The most common monogenic causes were partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS. A germline SASH3 nonsense mutation (c.862C>T; p.Arg288Ter) has been identified as a specific monogenic cause. By contrast, an adult chronic ITP/Evans cohort (n=44) screened with an NGS panel of >370 IEI genes found no fully penetrant IEI, though 18.2% carried heterozygous pathogenic IEI variants — establishing that the diagnostic yield of IEI testing is far higher in pediatric than adult-onset disease.

"Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS." — PMID: 41560547 "No cases of IEI were identified despite a high representation of subjects with a personal history of autoimmunity" — PMID: 37792884 "identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI" — PMID: 37646304

F003 — Chronic, relapsing, multisystem course with ~16% pediatric mortality at 15 years

In the French OBS'CEREVANCE cohort of 151 pediatric-onset ES patients with >5 years follow-up (median 11.3 years): at 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% respectively; by age 20, 74% had ≥1 clinical immunopathological manifestation (lymphoproliferation, dermatological, GI/hepatic, pulmonary). Survival at 15 years was 84% (~16% mortality); death occurred at a median age of 18 years, most often from infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In an earlier cohort (n=156), 5-year ITP and AIHA relapse-free survival were 25% and 61%, and 69% required ≥1 second-line treatment.

"At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively." — PMID: 33440924 "Survival at 15 years after diagnosis was 84%." — PMID: 33440924 "Overall, 69% of children required one or more second-line immune treatments" — PMID: 26484337

F004 — Treatment: corticosteroids/IVIG first-line; rituximab and sirolimus effective second-line

Standard first-line therapy is corticosteroids ± IVIG, but relapse on taper is common. Rituximab (anti-CD20): in a prospective French pediatric AIHA/Evans cohort (n=61), 75% responded and rituximab allowed steroid withdrawal in 72%; 6-year relapse-free survival was 48% (higher in isolated AIHA than in ES, P<0.05). Sirolimus (mTOR inhibitor): in a multicenter prospective trial of 30 refractory AICs, all 12 ALPS children achieved durable complete response and most patients with Evans syndrome/CVID/SLE responded. Genotype-directed targeted agents are emerging (abatacept for CTLA4/LRBA; sirolimus/leniolisib for ALPS/APDS; ruxolitinib/baricitinib). Splenectomy is effective but its benefit is diminished by immunopathological manifestations and carries infection/thrombosis risk.

"Forty-six patients responded (75%) and the 6-year relapse-free survival (RFS) was 48%." — PMID: 28444729 "sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias" — PMID: 26504182

F005 — ANA-positive childhood ES is a strong risk factor for progression to SLE

In the OBS'CEREVANCE cohort, ANA were positive in 20% (355/1803) of children with AIC; 22% of ANA-positive patients developed SLE at a median age of 14.5 years. Progression to SLE occurred in 45% of ANA-positive Evans syndrome patients (vs 20% chronic ITP, 19% AIHA); no ANA-negative patient developed SLE. Independent risk factors were age >10 years at AIC diagnosis (RR 3.67, 95% CI 1.18–11.4, P=.024) and ANA titer >1/160 (RR 5.28, 95% CI 1.20–23.17, P=.027).

"20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome" — PMID: 38227934

F006 — Very rare, rising incidence; secondary ES has markedly worse survival

Danish nationwide registry data. Adults (n=242, 1977–2017): mean age at diagnosis 58.5 years, 51.2% women, 27.3% secondary; incidence rose to 1.8 per million person-years and prevalence to 21.3 per million persons by 2016. Median survival was 7.2 years overall (primary 10.9 years; secondary only 1.7 years; secondary 5-year survival 38%); leading causes of death were bleeding, infections, and hematological cancer. Children <13 years (n=21): incidence 0.5–1.2 per million person-years; prevalence rose from 6.7 (1990) to 19.3 (2015) per million; hazard ratio for death was 22-fold higher than matched general-population children.

"The annual Evans syndrome incidence and prevalence rose significantly during the study period, to 1.8 per million person-years and 21.3 per million persons, respectively, in 2016." — PMID: 31292991 "The median survival with Evans syndrome was 7.2 years (primary Evans syndrome: 10.9 years; secondary Evans syndrome: 1.7 years)." — PMID: 31292991 "Hazard ratio for death was 22 fold higher for children with ES compared to matched children from general population" — PMID: 32271826

F007 — Mechanism: defective lymphocyte apoptosis / broken tolerance → autoantibody-mediated cytopenias

A large subset of ES — particularly ALPS — results from defective FAS-mediated extrinsic apoptosis of lymphocytes (germline/somatic FAS, FASLG, CASP10), leading to lymphoproliferation, expansion of TCRαβ+ CD4−CD8− double-negative T (DNT) cells, and autoimmune cytopenias. ALPS biomarkers include elevated DNT cells and elevated soluble FAS ligand (sFASL). Other monogenic causes disrupt tolerance at distinct nodes: CTLA4/LRBA (impaired Treg checkpoint), PIK3CD (APDS, PI3K-δ hyperactivation), NFKB1 (haploinsufficiency), and SASH3 (lymphocyte adaptor; germinal-center hypoplasia). The final common step is warm IgG anti-erythrocyte and anti-platelet-glycoprotein autoantibody production causing Fc-receptor/complement-mediated splenic destruction.

"Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway." — PMID: 22157362 "sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds" — PMID: 38700373 "LRBA protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS)" — PMID: 31432443

F008 — Clinical phenotype and diagnostic laboratory profile

The phenotype combines features of both cytopenias. AIHA component (HP:0004808): pallor (HP:0000980), fatigue (HP:0012378), jaundice (HP:0000952), dark urine, splenomegaly (HP:0001744); labs show positive DAT (warm IgG±C3d — 74% IgG/IgG+C3d in the pediatric cohort), reticulocytosis, elevated LDH and indirect bilirubin, low haptoglobin. ITP component (HP:0001973): petechiae (HP:0000967), purpura/bruising (HP:0000979), mucosal/GI bleeding (HP:0011897). When ES reflects immune dysregulation, organomegaly is prominent — in LRBA deficiency splenomegaly occurred in 93.3% (14/15). Some patients also have neutropenia (HP:0001875), hypogammaglobulinemia (HP:0004313), and recurrent infections (HP:0002719).

"In 74% of cases the direct antiglobulin test was IgG/IgG+C3d." — PMID: 21228033 "Splenomegaly was seen in 93.3% (14/15) of the patients on admission." — PMID: 31432443

F009 — Natural disease in dogs; FAS-pathway (Fas^lpr) mouse model

Natural disease: ES (concurrent immune-mediated hemolytic anemia + immune-mediated thrombocytopenia) is a recognized spontaneous entity in the domestic dog (Canis lupus familiaris, NCBI:txid9615), reported across breeds including Rottweiler, Miniature Schnauzer, and Dachshund; canine cases are DAT-positive, glucocorticoid/immunosuppressant-responsive, and can be complicated by thrombosis and opportunistic infection — paralleling human disease. Model organism: the FAS pathway underlying ALPS-type human ES is modeled by the MRL/lpr (Fas^lpr) and gld (Faslg) mouse, which develop lymphoproliferation, TCRαβ+ DNT-cell accumulation, autoantibodies, and autoimmune cytopenias; leniolisib reduced lymphoproliferation in murine ALPS.

"presumptively diagnosed with Evans' syndrome (ES)" — PMID: 19411652 "Leniolisib reduced lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome" — PMID: 41608120

The 15-Section Disease Characteristics Report

1. Disease Information

Overview. Evans syndrome is a rare, chronic autoimmune disorder characterized by the combination of AIHA and ITP (± autoimmune neutropenia), occurring simultaneously or sequentially (F001). It is a diagnosis of exclusion made after ruling out secondary causes (SLE, lymphoproliferative disease, IEI, drugs, infection).

Key identifiers: | Resource | Identifier | |---|---| | MONDO | MONDO:0016030 | | Orphanet | ORPHA:1959 | | ICD-10 | D69.3 (ITP component) / D59.1 (AIHA component) — no single dedicated code | | ICD-11 | 3B51.0 / 3A20 (component-based) | | MeSH | Anemia, Hemolytic, Autoimmune; Thrombocytopenia (no unique ES MeSH heading) | | OMIM | No single OMIM entry; monogenic causes have their own (e.g., ALPS 601859; CTLA4 haploinsufficiency 616100; APDS 615513) |

Synonyms: Evans-Fisher syndrome; autoimmune hemolytic anemia with immune thrombocytopenia; combined autoimmune hemolytic anemia and thrombocytopenia.

Information source. Evidence in this report derives from aggregated disease-level resources: national prospective cohorts (French OBS'CEREVANCE), nationwide registries (Danish), and case series/reports — not from a single EHR extract.

2. Etiology

Causal factors. ES is heterogeneous. It may be primary (idiopathic) or secondary to another disorder. A dominant paradigm is that ES is often the hematologic expression of an underlying inborn error of immunity (F002, F007). Documented monogenic/genetic causes: FAS, FASLG, CASP10 (ALPS), CTLA4, LRBA (Treg checkpoint defects), PIK3CD (APDS), NFKB1 (haploinsufficiency), SASH3, and partial DiGeorge syndrome (22q11.2 deletion). Secondary causes include SLE, common variable immunodeficiency, and lymphoproliferative disease.

Genetic risk factors. Germline loss-of-function variants in the genes above; somatic FAS variants in ALPS; the 22q11.2 microdeletion (pDGS). ANA positivity marks a susceptibility state for SLE-associated ES (F005).

Environmental risk factors. Age (bimodal: pediatric and older-adult peaks), female sex (adult 51.2% women), family/personal history of autoimmunity. No established toxin, occupational, or dietary cause. Some secondary cases follow infection or lymphoma.

Protective factors. None specifically established. ANA-negativity predicts against SLE progression (F005). No protective genetic alleles are defined for ES.

Gene–environment interactions. In ANA-positive children, age >10 years plus high ANA titer (>1/160) multiplicatively raise SLE risk (F005), illustrating interaction between an autoantibody "environment" and host age/genetic background. Not otherwise well characterized.

3. Phenotypes

Phenotype	Type	HPO term	Frequency / notes
Autoimmune hemolytic anemia	Lab/clinical	HP:0004808	Defining; DAT+ in ~all; 74% IgG/IgG+C3d
Autoimmune thrombocytopenia	Lab/clinical	HP:0001973	Defining
Pallor	Sign	HP:0000980	Common (anemia)
Fatigue	Symptom	HP:0012378	Common
Jaundice	Sign	HP:0000952	Hemolysis
Splenomegaly	Sign	HP:0001744	Very common in immune-dysregulation ES; 93.3% in LRBA deficiency
Petechiae	Sign	HP:0000967	Thrombocytopenic bleeding
Purpura/bruising	Sign	HP:0000979	Common
Mucosal/GI bleeding	Sign	HP:0011897	Variable severity
Lymphadenopathy	Sign	HP:0002716	ALPS-type ES
Neutropenia	Lab	HP:0001875	Subset (triple cytopenia)
Hypogammaglobulinemia	Lab	HP:0004313	IEI-associated
Recurrent infections	Clinical	HP:0002719	IEI-associated; major cause of death

Characteristics. Onset spans neonatal to geriatric; pediatric-onset disease is typically chronic and relapsing (F003), adult disease often chronic. Severity is variable to severe (life-threatening anemia or bleeding possible). Progression is episodic/relapsing-remitting. By age 20, 74% of pediatric-onset patients have ≥1 additional immunopathological manifestation (F003).

Quality-of-life impact. High treatment burden, chronic relapses, transfusion dependence in flares, immunosuppression-related infection risk, and cumulative organ involvement substantially impair QoL; formal EQ-5D/SF-36/PROMIS data specific to ES were not identified (knowledge gap).

4. Genetic / Molecular Information

Causal genes (in monogenic/IEI-associated ES): FAS (OMIM 134637), FASLG, CASP10, CTLA4, LRBA, PIK3CD, NFKB1, SASH3; chromosomal 22q11.2 deletion (partial DiGeorge) (F002, F007).

Pathogenic variants. Documented examples include the SASH3 nonsense variant c.862C>T (p.Arg288Ter) (F002). Variant classes span nonsense/frameshift (loss of function; NFKB1, LRBA, SASH3), missense (gain of function in PIK3CD/APDS), and structural (22q11.2 deletion). ALPS may involve somatic FAS variants restricted to DNT cells as well as germline variants. Functional consequences: loss of function (FAS apoptosis, LRBA/CTLA4 checkpoint, NFKB1), gain of function (PIK3CD/PI3K-δ hyperactivation).

Modifier genes. Not formally established for ES; disease expression is modified by the specific IEI genotype and by secondary triggers (SLE, lymphoma).

Epigenetic information. No ES-specific DNA-methylation or histone-modification signature was identified in the literature reviewed (knowledge gap).

Chromosomal abnormalities. 22q11.2 deletion (partial DiGeorge) is the single most common monogenic-level cause in one large pediatric AIC cohort (F002).

5. Environmental Information

Environmental factors. No established chemical, radiation, or occupational cause. Infectious agents may act as triggers in secondary ES, and infections are a leading complication/cause of death, but no single pathogen is causal. Lifestyle factors are not established causes; comorbidities such as diabetes and heavy smoking appear in case reports of thrombotic complications but are not disease causes. ES itself is autoimmune, not infectious or transmissible.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A germline (or somatic) genetic lesion in a tolerance/apoptosis gene — e.g., FAS/FASLG/CASP10, CTLA4, LRBA, PIK3CD, NFKB1, SASH3 — leads to defective lymphocyte homeostasis or a broken immune checkpoint (upstream; demonstrated for these IEIs). In primary/idiopathic ES without an identified gene, this step is inferred.
Branch A (ALPS-type): defective FAS-mediated extrinsic apoptosis results in failure to delete autoreactive lymphocytes → lymphoproliferation and accumulation of TCRαβ+ CD4−CD8− double-negative T (DNT) cells (demonstrated; DNT cells and elevated soluble FASL are diagnostic biomarkers).
Branch B (checkpoint-type): CTLA4/LRBA loss, PI3K-δ hyperactivation (APDS), or NFKB1 haploinsufficiency results in impaired regulatory T-cell function and dysregulated B/T-cell activation.
Both branches converge on loss of B-cell tolerance and results in activation of autoreactive B cells / plasma cells.
This leads to production of warm IgG autoantibodies against red-cell antigens and anti-platelet glycoprotein (e.g., GPIIb/IIIa) antibodies (demonstrated effector step).
Autoantibody opsonization results in Fc-receptor– and complement-mediated phagocytosis/destruction of erythrocytes and platelets, predominantly by splenic macrophages (downstream effector).
This leads to the clinical manifestations: hemolytic anemia (pallor, jaundice, reticulocytosis, low haptoglobin, high LDH/bilirubin) and thrombocytopenia (petechiae, purpura, bleeding) (F007, F008).

 Genetic lesion (FAS/CTLA4/LRBA/PIK3CD/NFKB1/SASH3 or unknown)
  │
   ┌──────┴───────────┐
   ▼                   ▼
 Defective FAS       Impaired Treg / checkpoint
 apoptosis (ALPS)    (CTLA4, LRBA, APDS, NFKB1)
   │  DNT-cell         │
   │  expansion        │
   └──────┬────────────┘
  ▼
  Loss of B-cell tolerance → autoreactive plasma cells
  ▼
  Warm IgG anti-RBC + anti-platelet autoantibodies
  ▼
  Fc-receptor / complement-mediated splenic destruction
  ▼
  AIHA + ITP  (Evans syndrome)

Molecular pathways: FAS/FASLG extrinsic apoptosis (caspase-8/10); PI3K-AKT-mTOR (APDS; rationale for sirolimus/leniolisib); CTLA4–CD80/86 costimulation checkpoint; NF-κB signaling. Cellular processes: defective apoptosis, lymphoproliferation, breakdown of self-tolerance, complement activation, macrophage phagocytosis. Immune involvement: combined autoimmunity + immunodeficiency (recurrent infection). GO terms: apoptotic process (GO:0006915), regulation of immune response (GO:0050776), complement activation (GO:0006956), phagocytosis (GO:0006909). Cell types (CL): double-negative T cell, regulatory T cell (CL:0000815), B cell/plasma cell (CL:0000786), macrophage (CL:0000235), erythrocyte (CL:0000232), platelet/thrombocyte (CL:0000233).

7. Anatomical Structures Affected

Organ level. Primary: spleen (UBERON:0002106; principal site of destruction and often enlarged), bone marrow (UBERON:0002371; compensatory hyperplasia), blood (UBERON:0000178). Secondary/associated: lymph nodes (UBERON:0000029; lymphoproliferation), liver (UBERON:0002107; hepatomegaly, associated autoimmune hepatitis), lungs and GI tract in multisystem ES. Body systems: hematopoietic/immune (primary), with cardiovascular (thrombosis risk), hepatic, pulmonary, and GI involvement in immune-dysregulation subtypes.

Tissue/cell level. Targets: erythrocytes (CL:0000232) and platelets (CL:0000233); effectors: splenic macrophages (CL:0000235), dysregulated T cells (including DNT cells) and B cells/plasma cells.

Subcellular level. Death-inducing signaling complex at the plasma membrane (FAS/FADD/caspase); autoantibody targets are red-cell membrane proteins and platelet-surface glycoproteins. GO cellular components: plasma membrane (GO:0005886), death-inducing signaling complex (GO:0031264).

Localization. Systemic; splenic destruction is central. Lateralization not applicable (systemic hematologic disease).

8. Temporal Development

Onset. Bimodal — pediatric (childhood) and older-adult (mean 58.5 years in the Danish adult cohort). Onset pattern is typically subacute to chronic/insidious, though acute severe hemolytic or bleeding crises occur. The two cytopenias may present simultaneously or years apart (F001).

Progression. Relapsing-remitting/episodic, chronic lifelong course (F003). Pediatric 5-year relapse-free survival: ITP 25%, AIHA 61%. At 10 years, sustained CR in 54.5% (ITP) and 78.4% (AIHA). Multisystem immunopathology accrues over time (74% by age 20).

Patterns. Remissions are usually treatment-induced; spontaneous durable remission is uncommon in pediatric-onset disease. Critical windows: early diagnosis of an underlying IEI opens the door to genotype-targeted therapy; monitoring for immunopathological manifestations refines splenectomy risk–benefit.

9. Inheritance and Population

Epidemiology (F006). Adult incidence ~1.8 per million person-years, prevalence ~21.3 per million (Denmark, 2016). Pediatric incidence 0.5–1.2 per million person-years; pediatric prevalence rising (6.7→19.3 per million, 1990→2015). Adult mean age at diagnosis 58.5 years; 51.2% women; 27.3% secondary.

Genetic etiology. Inheritance depends on the underlying IEI: autosomal dominant (ALPS/FAS, CTLA4 haploinsufficiency, NFKB1, PIK3CD GOF), autosomal recessive (LRBA), X-linked (SASH3), or de novo/structural (22q11.2 deletion). Penetrance is incomplete and age-dependent (e.g., CTLA4 haploinsufficiency). Expressivity is variable. Somatic mosaicism occurs in ALPS (somatic FAS variants). Anticipation, founder effects, and consanguinity are not general features of ES, though consanguinity increases recessive-IEI (LRBA) risk. Most "primary" ES has no identified single gene and behaves as a multifactorial/polygenic autoimmune trait.

Population demographics. No strong ethnic predilection established; adult female predominance is modest (~51%). Geographic distribution is worldwide; rising recorded incidence likely reflects better ascertainment.

10. Diagnostics

Clinical/laboratory tests (F008). CBC with blood smear (spherocytes, polychromasia, low platelets); direct antiglobulin (Coombs) test (warm IgG ± C3d; 74% IgG/IgG+C3d); reticulocyte count (elevated); LDH (elevated), indirect/unconjugated bilirubin (elevated), haptoglobin (low); platelet count (low). LOINC-codable analytes: hemoglobin, platelet count, reticulocytes, LDH, bilirubin, haptoglobin, DAT.

Biomarkers. For underlying ALPS: elevated TCRαβ+ DNT cells and soluble FAS ligand (sFASL); also elevated vitamin B12 and IL-10 in ALPS. ANA (SLE risk marker). Immunoglobulin levels (hypogammaglobulinemia in IEI).

Genetic testing. Given the high IEI yield in pediatric ES (F002), NGS gene panels (>370 IEI genes), whole-exome sequencing, and increasingly whole-genome sequencing are recommended, especially in children, early-onset, syndromic, or treatment-refractory cases. Chromosomal microarray/FISH for 22q11.2 deletion (partial DiGeorge). Targeted single-gene testing when a specific IEI is suspected. Adult isolated ES has lower monogenic yield.

Clinical criteria & differential diagnosis. Diagnosis is clinical + laboratory (coexistent AIHA and ITP with positive DAT) after exclusion of: thrombotic thrombocytopenic purpura / thrombotic microangiopathy (check ADAMTS13; <10 IU/dL indicates iTTP), SLE, drug-induced cytopenias, lymphoproliferative disease, DIC, and hemophagocytic syndrome. Microangiopathic hemolysis with schistocytes distinguishes TMA from the warm-antibody hemolysis of ES.

Screening. No population screening. Cascade genetic screening of relatives is appropriate when a monogenic IEI is identified. No newborn screening for ES.

11. Outcome / Prognosis

Survival/mortality (F003, F006). Adult median survival 7.2 years (primary 10.9 years; secondary only 1.7 years, 5-year survival 38%). Pediatric survival at 15 years 84% (~16% mortality), death at median age 18 years; pediatric HR for death 22× the general population. Leading causes of death: infection, bleeding, and hematological cancer.

Morbidity/function. High — chronic relapses, transfusion dependence during flares, cumulative multisystem immunopathology, and immunosuppression-related complications. Disease-specific QoL instruments were not identified (gap).

Complications. Recurrent/severe infections (major driver of mortality), thrombosis (including reports of Buerger's disease and spontaneous echocardiographic contrast), hematological malignancy, and progression to SLE.

Prognostic factors. Independent predictors of mortality: number of second-line treatments and severe/recurrent infections (F003). Secondary etiology predicts markedly worse survival (F006). ANA positivity + age >10 + high titer predicts SLE progression (F005). Immunopathological manifestations reduce splenectomy benefit.

12. Treatment

Line	Intervention	Evidence / notes	NCIT
First	Corticosteroids (prednisone/prednisolone) ± IVIG	Standard; relapse common on taper (F004)	NCIT:C305 (steroid); NCIT:C555 (IVIG)
Second	Rituximab (anti-CD20)	75% response, 72% steroid withdrawal, 6-yr RFS 48% (F004)	NCIT:C1702
Second	Sirolimus (mTOR inhibitor)	Durable CR in refractory multilineage AIC, all ALPS children (F004)	NCIT:C1212
Second/other	Mycophenolate mofetil, azathioprine	Effective in ES + autoimmune hepatitis case reports	NCIT:C2005 / NCIT:C264
Targeted	Abatacept (CTLA4-Ig)	For CTLA4/LRBA defects	NCIT:C65483
Targeted	Leniolisib / sirolimus	For APDS/ALPS (PI3K-δ pathway); leniolisib validated in murine ALPS	—
Targeted	Ruxolitinib / baricitinib (JAK inhibitors)	Immune dysregulation subtypes	—
Complement/other	Iptacopan (factor B inhibitor)	Refractory C3d-positive AIHA flares (case reports)	—
Surgical	Splenectomy	Effective but benefit reduced by immunopathological manifestations; infection/thrombosis risk	NCIT:C51915
Cellular	Hematopoietic stem cell transplant	For severe monogenic IEI-associated ES	NCIT:C15431

Pharmacogenomics/personalized medicine. Genotype-directed therapy is a defining trend: abatacept for CTLA4/LRBA, sirolimus/leniolisib for ALPS/APDS, JAK inhibitors for interferon/JAK-STAT–driven dysregulation. Treatment strategy: escalate from steroids/IVIG → rituximab/sirolimus → genotype-targeted agents; reserve splenectomy for selected cases; support with transfusion, infection prophylaxis, and thrombosis awareness.

13. Prevention

Primary prevention: none (no modifiable cause). Secondary prevention: early recognition of coexistent cytopenias and prompt immunosuppression; early IEI genetic diagnosis enables targeted therapy and family counseling. Tertiary prevention: infection prophylaxis (vaccination, especially before/after splenectomy — encapsulated-organism vaccines; antibiotic prophylaxis post-splenectomy), thrombosis vigilance, monitoring for SLE progression and malignancy, and surveillance for accruing immunopathological manifestations. Genetic counseling is indicated when a monogenic IEI is found (variable inheritance patterns). No immunization prevents ES itself.

14. Other Species / Natural Disease

Taxonomy. Naturally occurring ES is well documented in the domestic dog (Canis lupus familiaris, NCBI:txid9615) — concurrent immune-mediated hemolytic anemia and immune-mediated thrombocytopenia (F009). Reported breeds: Rottweiler, Miniature Schnauzer, Dachshund. Canine cases are DAT-positive and glucocorticoid/immunosuppressant-responsive, and can be complicated by thrombosis and opportunistic infection during immunosuppression — closely paralleling human disease.

Orthologous genes. FAS, FASLG, CTLA4, LRBA, PIK3CD orthologs are conserved across mammals. Comparative biology: the FAS apoptosis mechanism is evolutionarily conserved, underpinning both canine natural disease and rodent models. Zoonotic potential: none (autoimmune, non-transmissible).

15. Model Organisms

Model type. Mammalian (mouse) genetic models of the FAS pathway recapitulate ALPS-type ES (F009). Specific systems: MRL/lpr (Fas^lpr) mouse (Fas loss of function) and gld (Faslg) mouse (FAS ligand defect) — both develop lymphoproliferation, TCRαβ+ DNT-cell accumulation, autoantibodies, and autoimmune cytopenias.

Applications. These models study the apoptosis-defect mechanism, DNT-cell biology, and therapeutics — e.g., leniolisib reduced lymphoproliferative disease in murine ALPS (F009), validating targeted therapy translation. Limitations: lpr/gld mice best model the ALPS/FAS subtype and background-dependent lupus-like autoimmunity; they do not capture the full heterogeneity of human ES (CTLA4, LRBA, APDS, NFKB1, SASH3, secondary ES). Resources: MGI, IMSR for Fas/Faslg alleles.

Mechanistic Model / Interpretation

Evans syndrome should be conceptualized as a shared downstream phenotype produced by many upstream lesions of immune tolerance. The unifying "trunk" is autoantibody-mediated, Fc-receptor/complement-driven splenic destruction of red cells and platelets. The "roots" are diverse: defective apoptosis (ALPS/FAS pathway), failed Treg checkpoints (CTLA4/LRBA), signaling hyperactivation (PIK3CD/APDS), transcriptional haploinsufficiency (NFKB1), adaptor loss (SASH3), or a structural syndrome (22q11.2/pDGS) — and, in a large fraction, no identifiable single gene (polygenic/multifactorial autoimmunity), or a secondary driver (SLE, lymphoma).

This model explains the clinical behavior: because the root cause is systemic immune dysregulation, ES is rarely "just" a blood disease — it tends to recruit additional autoimmune and lymphoproliferative manifestations over time (74% by age 20), progresses to SLE in high-risk ANA-positive children, relapses despite treatment, and kills primarily through infection (reflecting the immunodeficiency side of the dysregulation) and bleeding. It also explains why therapy is migrating from broad immunosuppression toward mechanism-matched targeted agents (abatacept, sirolimus/leniolisib, JAK inhibitors), which requires molecular diagnosis via genomic sequencing.

Evidence Base

PMID	Study	Supports
31983745	ES case report/review	Definition, autoantibody mechanism (F001, F008)
21228033	French AIHA cohort (n=265)	37% ES frequency; 74% IgG/IgG+C3d DAT (F001, F008)
41560547	Prospective AIC biomarker study (n=104)	51% IEI, 26% monogenic; pDGS/NFKB1/CTLA4/FAS (F002)
37792884	Adult ITP/Evans IEI screen (n=44)	Low adult monogenic yield (F002)
37646304	SASH3 case	Novel monogenic cause (F002)
33440924	OBS'CEREVANCE long-term (n=151)	Remission rates, 84% 15-yr survival, mortality factors (F003)
26484337	OBS'CEREVANCE cohort (n=156)	High treatment burden (F003)
28444729	Rituximab pediatric cohort (n=61)	75% response, 72% steroid withdrawal (F004)
26504182	Sirolimus prospective trial (n=30)	Sirolimus efficacy in refractory AIC (F004)
38227934	ANA-associated AIC study	45% ES→SLE; risk factors (F005)
31292991	Danish adult registry (n=242)	Incidence/prevalence; primary vs secondary survival (F006)
32271826	Danish pediatric cohort (n=21)	Pediatric incidence; 22× mortality HR (F006)
22157362	ALPS review	FAS apoptosis mechanism (F007)
38700373	ALPS biomarker study	sFASL/DNT biomarkers (F007)
31432443	LRBA defect series	LRBA tolerance mechanism; 93.3% splenomegaly (F007, F008)
19411652	Canine ES case	Natural disease in dog (F009)
41608120	Murine ALPS + leniolisib	Mouse model + targeted therapy (F009)
35443028	Splenectomy outcomes	Immunopathological manifestations reduce splenectomy benefit
40809448	Microangiopathic anemia review	TTP/TMA differential (ADAMTS13)

Limitations and Knowledge Gaps

No dedicated OMIM/ICD entry: ES is coded by its components; identifiers are inherited from underlying IEIs, complicating standardized annotation.
Adult vs pediatric divergence: monogenic IEI yield is high in children but low in adults; conclusions from pediatric cohorts may not transfer to adult-onset disease.
QoL data absent: no ES-specific EQ-5D/SF-36/PROMIS evidence was identified.
Epigenetics unstudied: no ES-specific methylation/histone or single-cell/spatial multi-omics signature was found in the reviewed literature.
Primary/idiopathic ES mechanism inferred: for the large fraction lacking an identified gene, the tolerance-defect chain is extrapolated from monogenic cases, not directly demonstrated.
Two citation snippets were flagged "mismatch" in the knowledge state (PMID 37008642, 41608120 — title-based); their claims (canine ES; murine ALPS + leniolisib) are corroborated by companion verified citations but should be re-verified against full text.
Treatment evidence is largely from cohorts, single-arm trials, and case reports; randomized comparative data are scarce given rarity.

Proposed Follow-up Experiments / Actions

Systematic genomic testing study stratified by age of onset to define IEI yield thresholds and cost-effectiveness of WES/WGS in adult vs pediatric ES.
Prospective biomarker panel (DNT cells, sFASL, ANA titer, IL-10, immunoglobulins) to build a validated risk-stratification model for SLE progression, malignancy, and mortality.
Genotype-stratified therapeutic trials matching targeted agents to mechanism (abatacept for CTLA4/LRBA; leniolisib for APDS; JAK inhibitors for interferonopathy-like dysregulation).
Single-cell and spatial immune profiling of spleen/marrow/blood to map the autoreactive B-cell and DNT-cell compartments and identify novel targets.
ES-specific QoL/PRO instrument development and longitudinal capture within existing registries (OBS'CEREVANCE, Danish).
Comparative canine studies leveraging naturally occurring canine ES as a translational large-animal model for therapeutics.

Report compiled from 9 confirmed findings and 34 reviewed papers across 5 investigation iterations. Evidence source types: predominantly human clinical (national cohorts, registries, case series), with model-organism (Fas^lpr/gld mouse) and natural-disease (canine) corroboration.

Artifacts

Citations

PMID:31983745
PMID:21228033
PMID:41560547
PMID:37792884
PMID:37646304
PMID:33440924
PMID:26484337
PMID:28444729
PMID:26504182
PMID:38227934
PMID:31292991
PMID:32271826
PMID:22157362
PMID:38700373
PMID:31432443
PMID:19411652
PMID:41608120

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Epidemiology

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References & Deep Research

References

Deep Research

Evans Syndrome: A Comprehensive Disease Characteristics Report

Summary

Key Findings

F001 — Definition: coexistence of AIHA and ITP

F002 — Frequently the presenting sign of an inborn error of immunity (IEI)

F003 — Chronic, relapsing, multisystem course with ~16% pediatric mortality at 15 years

F004 — Treatment: corticosteroids/IVIG first-line; rituximab and sirolimus effective second-line

F005 — ANA-positive childhood ES is a strong risk factor for progression to SLE

F006 — Very rare, rising incidence; secondary ES has markedly worse survival

F007 — Mechanism: defective lymphocyte apoptosis / broken tolerance → autoantibody-mediated cytopenias

F008 — Clinical phenotype and diagnostic laboratory profile

F009 — Natural disease in dogs; FAS-pathway (Fas^lpr) mouse model

The 15-Section Disease Characteristics Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Citations